Is DNAJA3 p.Arg461His (c.1382G>A) pathogenic?

DNAJA3 p.Arg461His (c.1382G>A) is classified Uncertain significance in DNAJA3 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-16). AlphaMissense: likely benign (0.1227); Ultra-rare (popmax 0.0219%, nfe).

How common is DNAJA3 p.Arg461His (c.1382G>A) in the general population?

DNAJA3 p.Arg461His (c.1382G>A) is ultra-rare (popmax 0.0219%, nfe) (gnomAD).

What do computational predictors say about DNAJA3 p.Arg461His (c.1382G>A)?

AlphaMissense predicts likely benign (score 0.1227) — an in-silico prediction, not a clinical call.

DNAJA3 p.Arg461His

c.1382G>A · rs61758418 · VCV2354266

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1227 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0219%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1227	likely benign
REVEL	0.091	moderately benign-leaning
SaProt	LLR -7.94	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 0.85	GERP -3.5, phastCons 0.36
Regional constraint	o/e 1.11	unconstrained · MANE · 29 kb · p 0.0067 · regional, not allelic
Overall
CADD	18.58	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 0.0219% European (non-Finnish) · 258/1,179,990 alleles

Filtering AF 0.0196% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0188%

Overall 0.0178% 287/1,614,128 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0219%	4,574
Admixed American	0.0117%	8,575
Remaining individualsnot grpmax-eligible	0.0112%	8,929
East Asian	0.00891%	11,221
African / African-American	0.00666%	15,010
Finnishnot grpmax-eligible	0.00625%	16,010
South Asian	0.0022%	45,540

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: DNAJA3
Protein: p.Arg461His
Coding: c.1382G>A
MANE Select: NM_005147
dbSNP: rs61758418
Type: single nucleotide variant
Location: chr16:4454853 (GRCh38)
Gene constraint: LOEUF 0.737 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.04 · 4 PDB
Residue 461: the 'disordered' region

Full DNAJA3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAJA3 p.Ala112Val Uncertain significance ★ ⚠ same type
DNAJA3 p.Ala21Thr Uncertain significance ★ ⚠ same type
DNAJA3 p.Ala344Thr Uncertain significance ★ ⚠ same type
DNAJA3 p.Ala355Val Uncertain significance ★ ⚠ same type
DNAJA3 p.Ala357Thr Uncertain significance ★ ⚠ same type
DNAJA3 p.Ala365Thr Uncertain significance ★ ⚠ same type
DNAJA3 p.Ala3Val Uncertain significance ★ ⚠ same type
DNAJA3 p.Ala455Thr 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/dnaja3-p-arg461his (accessed [today's date]).

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