Is THBD p.Arg339His (c.1016G>A) pathogenic?

THBD p.Arg339His (c.1016G>A) is classified Uncertain significance in THBD (ClinVar, Single submitter, 1 submitter; last evaluated 2022-04-20). AlphaMissense: likely benign (0.0793); Very rare (popmax 0.00167%, amr).

How common is THBD p.Arg339His (c.1016G>A) in the general population?

THBD p.Arg339His (c.1016G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about THBD p.Arg339His (c.1016G>A)?

AlphaMissense predicts likely benign (score 0.0793) — an in-silico prediction, not a clinical call.

THBD p.Arg339His

c.1016G>A · rs746618505 · VCV2128456

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0793 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0793	likely benign
REVEL	0.325	indeterminate
SaProt	LLR -7.61	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -5.5	GERP -3.1
Regional constraint	o/e 1.04	unconstrained · MANE · 1,724 bp · p 0.25 · regional, not allelic
Overall
CADD	0.525	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 0.00167% Admixed American · 1/60,026 alleles

Overall 0.000186% 3/1,610,456 alleles · very rare exomes 3/1,458,142 · genomes 0/152,314 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,026
South Asian	0.0011%	91,086
European (non-Finnish)	8.47e-05%	1,180,018

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.Arg339His
Coding: c.1016G>A
MANE Select: NM_000361
dbSNP: rs746618505
Type: single nucleotide variant
Location: chr20:23048489 (GRCh38)
Gene constraint: LOEUF 1.938 · pLI 0.05 (gnomAD)
Structure: AlphaFold pLDDT 79.35 · 13 PDB
Residue 339: the egf-like 3; calcium-binding domain

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

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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-arg339his (accessed [today's date]).

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