Is THBD p.Ala473Val (c.1418C>T) pathogenic?

THBD p.Ala473Val (c.1418C>T) is classified Benign/Likely benign in THBD (ClinVar, Multiple submitters, 11 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.1005); Common (popmax 27.8%, eas) — too common for a highly-penetrant pathogenic allele; Associated with atypical hemolytic-uremic syndrome.

What condition is associated with THBD p.Ala473Val (c.1418C>T)?

THBD p.Ala473Val (c.1418C>T) is associated with atypical hemolytic-uremic syndrome, atypical hemolytic-uremic syndrome with thrombomodulin anomaly, thrombomodulin-related bleeding disorder (ClinVar).

How is Atypical hemolytic uremic syndrome inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about THBD p.Ala473Val (c.1418C>T)?

AlphaMissense predicts likely benign (score 0.1005) — an in-silico prediction, not a clinical call.

THBD p.Ala473Val

Q: How common is THBD p.Ala473Val (c.1418C>T) in the general population?

THBD p.Ala473Val (c.1418C>T) is common (popmax 27.8%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1418C>T · rs1042579 · VCV337883

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 11 submitters

AlphaMissense

likely benign

0.1005 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 27.8%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome

Computational evidence

Protein change
AlphaMissense	0.1005	likely benign
REVEL	0.168	moderately benign-leaning
SaProt	LLR -6.82	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.5	GERP -1.9, phastCons 0.019
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	5.105	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 27.8% East Asian · 12,463/44,800 alleles

Filtering AF 27.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 27.2%

Overall 18.5% 298,724/1,611,792 alleles · common exomes 275,414/1,459,508 · genomes 23,310/152,284 · joint denominator

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	28.8%	3
East Asiangrpmax	27.8%	4
European (non-Finnish)	19.1%	5
South Asian	17.8%	6
Admixed American	17.3%	6
Remaining individualsnot grpmax-eligible	17%	6
Amishnot grpmax-eligible	15.2%	7
Ashkenazi Jewishnot grpmax-eligible	7.41%	13
Middle Eastern	5.86%	17
African / African-American	4.59%	22

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: THBD
Protein: p.Ala473Val
Coding: c.1418C>T
MANE Select: NM_000361
dbSNP: rs1042579
Type: single nucleotide variant
Location: chr20:23048087 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 473: the egf-like 6; calcium-binding domain; a UniProt-annotated variant site (in); a β-strand

Full THBD gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

atypical hemolytic-uremic syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atypical hemolytic-uremic syndrome with thrombomodulin anomaly thrombomodulin-related bleeding disorder

For Atypical hemolytic uremic syndrome (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, Not applicable
Onset: All ages
Prevalence: 1-9 / 1 000 000 (United States)

Similar variants

THBD p.Cys537Ter Pathogenic/Likely pathogenic ★★ same condition
THBD p.Ala139Ser Uncertain significance ★★ ⚠ same condition
THBD p.Ala255Pro Uncertain significance ★★ ⚠ same condition
THBD p.Ala271Thr Uncertain significance ★★ ⚠ same condition
THBD p.Ala284Gly Uncertain significance ★★ ⚠ same condition
THBD p.Ala395Val Uncertain significance ★★ ⚠ same condition
THBD p.Ala471Thr Uncertain significance ★★ ⚠ same condition
THBD p.Ala545Thr Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/thbd-p-ala473val (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown