Is THBD p.Ala272Val (c.815C>T) pathogenic?

THBD p.Ala272Val (c.815C>T) is classified Uncertain significance in THBD (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-23). AlphaMissense: likely benign (0.0784); Very rare (popmax 0.00343%, amr); Associated with Inborn genetic diseases.

What condition is associated with THBD p.Ala272Val (c.815C>T)?

THBD p.Ala272Val (c.815C>T) is associated with Inborn genetic diseases (ClinVar).

How common is THBD p.Ala272Val (c.815C>T) in the general population?

THBD p.Ala272Val (c.815C>T) is very rare (popmax 0.00343%, amr) (gnomAD).

What do computational predictors say about THBD p.Ala272Val (c.815C>T)?

AlphaMissense predicts likely benign (score 0.0784) — an in-silico prediction, not a clinical call.

THBD p.Ala272Val

c.815C>T · rs764012702 · VCV2056606

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.0784 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00343%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0784	likely benign
REVEL	0.127	moderately benign-leaning
SaProt	LLR -5.46	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 -0.26	GERP -2.9
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	4.142	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 0.00343% Admixed American · 2/58,392 alleles

Filtering AF 0.000568% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000213%

Overall 0.000441% 7/1,585,742 alleles · very rare exomes 6/1,433,476 · genomes 1/152,266 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00343%	29,196
European (non-Finnish)	0.000426%	234,679

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.Ala272Val
Coding: c.815C>T
MANE Select: NM_000361
dbSNP: rs764012702
Type: single nucleotide variant
Location: chr20:23048690 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 272: 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

Similar variants

THBD p.Ala272Pro Uncertain significance ★ ⚠ same residue
THBD p.Ala21Ser Uncertain significance ★★ ⚠ same condition
THBD p.Ala255Pro 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-ala272val (accessed [today's date]).

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