Is THBD p.Arg403Lys (c.1208G>A) pathogenic?

THBD p.Arg403Lys (c.1208G>A) is classified Benign/Likely benign in THBD (ClinVar, Multiple submitters, 8 submitters; last evaluated 2026-04-20). AlphaMissense: likely benign (0.0877); Rare (popmax 0.497%, eas); Associated with atypical hemolytic-uremic syndrome with thrombomodulin anomaly.

How common is THBD p.Arg403Lys (c.1208G>A) in the general population?

THBD p.Arg403Lys (c.1208G>A) is rare (popmax 0.497%, eas) (gnomAD).

What do computational predictors say about THBD p.Arg403Lys (c.1208G>A)?

AlphaMissense predicts likely benign (score 0.0877) — an in-silico prediction, not a clinical call.

THBD p.Arg403Lys

Q: What condition is associated with THBD p.Arg403Lys (c.1208G>A)?

THBD p.Arg403Lys (c.1208G>A) is associated with atypical hemolytic-uremic syndrome with thrombomodulin anomaly, thrombomodulin-related bleeding disorder (ClinVar).

c.1208G>A · rs41400249 · VCV337884

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 8 submitters

AlphaMissense

likely benign

0.0877 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.497%, eas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

atypical hemolytic-uremic syndrome with thrombomodulin anomaly

Computational evidence

Protein change
AlphaMissense	0.0877	likely benign
REVEL	0.487	indeterminate
SaProt	LLR -6.55	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -2	GERP -2.1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	12.55	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 0.497% East Asian · 223/44,890 alleles

Filtering AF 0.443% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.423%

Overall 0.0387% 624/1,613,952 alleles · rare exomes 549/1,461,584 · genomes 75/152,368 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.497%	201
Admixed American	0.423%	236
South Asian	0.09%	1,111
Middle Eastern	0.0495%	2,021
Remaining individualsnot grpmax-eligible	0.0368%	2,718
African / African-American	0.012%	8,341
European (non-Finnish)	0.00254%	39,335

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.Arg403Lys
Coding: c.1208G>A
MANE Select: NM_000361
dbSNP: rs41400249
Type: single nucleotide variant
Location: chr20:23048297 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 403: a β-strand; the egf-like 4 domain

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

Disease context

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

Also linked: thrombomodulin-related bleeding disorder

Similar variants

THBD p.Arg403Ser Uncertain significance ★★ ⚠ same residue
THBD p.Cys537Ter Pathogenic/Likely pathogenic ★★ same condition
THBD p.Ala139Ser 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-arg403lys (accessed [today's date]).

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