Is THBD p.Asp244Gly (c.731A>G) pathogenic?

THBD p.Asp244Gly (c.731A>G) is classified Uncertain significance in THBD (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-02-19). AlphaMissense: likely benign (0.2835); Very rare (popmax 0.00407%, afr); Associated with atypical hemolytic-uremic syndrome with thrombomodulin anomaly.

How common is THBD p.Asp244Gly (c.731A>G) in the general population?

THBD p.Asp244Gly (c.731A>G) is very rare (popmax 0.00407%, afr) (gnomAD).

What do computational predictors say about THBD p.Asp244Gly (c.731A>G)?

AlphaMissense predicts likely benign (score 0.2835) — an in-silico prediction, not a clinical call.

THBD p.Asp244Gly

Q: What condition is associated with THBD p.Asp244Gly (c.731A>G)?

THBD p.Asp244Gly (c.731A>G) is associated with atypical hemolytic-uremic syndrome with thrombomodulin anomaly, thrombomodulin-related bleeding disorder (ClinVar).

c.731A>G · rs1347459395 · VCV2185383

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.2835 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00407%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

atypical hemolytic-uremic syndrome with thrombomodulin anomaly

Computational evidence

Protein change
AlphaMissense	0.2835	likely benign
REVEL	0.186	benign-leaning
SaProt	LLR -5.26	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 3	GERP 0.33, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	14.25	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00407% African / African-American · 3/73,704 alleles

Filtering AF 0.00108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0005%

Overall 0.000258% 4/1,550,134 alleles · very rare exomes 2/1,398,062 · genomes 2/152,072 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00407%	24,568
European (non-Finnish)	8.65e-05%	1,155,524

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.Asp244Gly
Coding: c.731A>G
MANE Select: NM_000361
dbSNP: rs1347459395
Type: single nucleotide variant
Location: chr20:23048774 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 244: the egf-like 1 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.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
THBD p.Arg101Leu 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-asp244gly (accessed [today's date]).

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