Is THBD p.Ala531Val (c.1592C>T) pathogenic?

THBD p.Ala531Val (c.1592C>T) is classified Conflicting classifications of pathogenicity in THBD (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-07-23). AlphaMissense: likely benign (0.1419); Ultra-rare (popmax 0.0164%, mid); Associated with Inborn genetic diseases.

What condition is associated with THBD p.Ala531Val (c.1592C>T)?

THBD p.Ala531Val (c.1592C>T) is associated with Inborn genetic diseases (ClinVar).

How common is THBD p.Ala531Val (c.1592C>T) in the general population?

THBD p.Ala531Val (c.1592C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about THBD p.Ala531Val (c.1592C>T)?

AlphaMissense predicts likely benign (score 0.1419) — an in-silico prediction, not a clinical call.

THBD p.Ala531Val

c.1592C>T · rs756102720 · VCV1423381

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1419 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1419	likely benign
REVEL	0.199	benign-leaning
SaProt	LLR -6.85	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 6.4	GERP 0.68, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	21.2	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 0.0164% Middle Eastern · 1/6,080 alleles

Filtering AF 0.00154% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0013%

Overall 0.00186% 30/1,609,538 alleles · ultra-rare exomes 28/1,457,286 · genomes 2/152,252 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,080
Admixed American	0.00505%	19,803
European (non-Finnish)	0.00221%	45,321

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.Ala531Val
Coding: c.1592C>T
MANE Select: NM_000361
dbSNP: rs756102720
Type: single nucleotide variant
Location: chr20:23047913 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB

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.Ala531Glu Likely benign ★ same residue
THBD p.Ala21Ser Uncertain significance ★★ ⚠ same condition
THBD p.Ala255Pro 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

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-ala531val (accessed [today's date]).

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