Is THBD p.Ala546Val (c.1637C>T) pathogenic?

THBD p.Ala546Val (c.1637C>T) is classified Uncertain significance in THBD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-02-24). AlphaMissense: likely benign (0.0971); Very rare (popmax 0.00112%, sas).

How common is THBD p.Ala546Val (c.1637C>T) in the general population?

THBD p.Ala546Val (c.1637C>T) is very rare (popmax 0.00112%, sas) (gnomAD).

What do computational predictors say about THBD p.Ala546Val (c.1637C>T)?

AlphaMissense predicts likely benign (score 0.0971) — an in-silico prediction, not a clinical call.

THBD p.Ala546Val

c.1637C>T · rs775722470 · VCV1978463

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0971 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00112%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0971	likely benign
REVEL	0.153	moderately benign-leaning
SaProt	LLR -7.61	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 -0.15	GERP -3.1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	5.64	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 0.00112% South Asian · 1/89,122 alleles

Overall 6.24e-05% 1/1,602,286 alleles · very rare exomes 1/1,449,914 · genomes 0/152,372 · joint denominator

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.Ala546Val
Coding: c.1637C>T
MANE Select: NM_000361
dbSNP: rs775722470
Type: single nucleotide variant
Location: chr20:23047868 (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

Similar variants

THBD p.Cys537Ter Pathogenic/Likely pathogenic ★★ same type
THBD p.Ala139Ser Uncertain significance ★★ ⚠ same type
THBD p.Ala21Ser Uncertain significance ★★ ⚠ same type
THBD p.Ala255Pro Uncertain significance ★★ ⚠ same type
THBD p.Ala271Thr Uncertain significance ★★ ⚠ same type
THBD p.Ala272Val Uncertain significance ★★ ⚠ same type
THBD p.Ala284Gly Uncertain significance ★★ ⚠ same type
THBD p.Ala395Val Uncertain significance ★★ ⚠ same type

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-ala546val (accessed [today's date]).

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