Is THBD p.Ala255Pro (c.763G>C) pathogenic?

THBD p.Ala255Pro (c.763G>C) is classified Uncertain significance in THBD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-24). AlphaMissense: likely benign (0.241); Very rare (popmax 0.00446%, nfe); Associated with Inborn genetic diseases.

What condition is associated with THBD p.Ala255Pro (c.763G>C)?

THBD p.Ala255Pro (c.763G>C) is associated with Inborn genetic diseases, atypical hemolytic-uremic syndrome (ClinVar).

How common is THBD p.Ala255Pro (c.763G>C) in the general population?

THBD p.Ala255Pro (c.763G>C) is very rare (popmax 0.00446%, nfe) (gnomAD).

What do computational predictors say about THBD p.Ala255Pro (c.763G>C)?

AlphaMissense predicts likely benign (score 0.241) — an in-silico prediction, not a clinical call.

THBD p.Ala255Pro

c.763G>C · rs1276712753 · VCV988131

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.241 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00446%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.241	likely benign
REVEL	0.376	indeterminate
SaProt	LLR -11.33	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.3	GERP -2.8
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	5.062	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 0.00446% European (non-Finnish) · 52/1,166,196 alleles

Filtering AF 0.00346% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00314%

Overall 0.0035% 55/1,569,352 alleles · very rare exomes 52/1,417,142 · genomes 3/152,210 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00446%	22,427
African / African-American	0.00269%	37,185
Remaining individualsnot grpmax-eligible	0.00164%	61,100

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.Ala255Pro
Coding: c.763G>C
MANE Select: NM_000361
dbSNP: rs1276712753
Type: single nucleotide variant
Location: chr20:23048742 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 255: the egf-like 1 domain

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: atypical hemolytic-uremic syndrome

Similar variants

THBD p.Ala255Val Uncertain significance ★ ⚠ same residue
THBD p.Ala21Ser Uncertain significance ★★ ⚠ same condition
THBD p.Ala272Val Uncertain significance ★★ ⚠ same condition
THBD p.Arg264His Uncertain significance ★★ ⚠ same condition
THBD p.Arg567Gln Uncertain significance ★★ ⚠ same condition
THBD p.Arg83Gly Uncertain significance ★★ ⚠ same condition
THBD p.Asn115Asp Uncertain significance ★★ ⚠ same condition
THBD p.Asn128Ser 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-ala255pro (accessed [today's date]).

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