Is DNAJA4 p.Asp65His (c.193G>C) pathogenic?

DNAJA4 p.Asp65His (c.193G>C) is classified Uncertain significance in DNAJA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-03). AlphaMissense: likely pathogenic (0.9816); Very rare (popmax 0.00223%, eas).

How common is DNAJA4 p.Asp65His (c.193G>C) in the general population?

DNAJA4 p.Asp65His (c.193G>C) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about DNAJA4 p.Asp65His (c.193G>C)?

AlphaMissense predicts likely pathogenic (score 0.9816) — an in-silico prediction, not a clinical call.

DNAJA4 p.Asp65His

c.193G>C · VCV4013488

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9816 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9816	likely pathogenic · top 9% in DNAJA4
REVEL	0.904	moderately pathogenic-leaning
SaProt	LLR -13.29	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 0.85, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 16 kb · p 0.0033 · regional, not allelic
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00223% East Asian · 1/44,886 alleles

Overall 6.84e-05% 1/1,461,878 alleles · very rare

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: DNAJA4
Protein: p.Asp65His
Coding: c.193G>C
MANE Select: NM_001130182
Type: single nucleotide variant
Location: chr15:78270557 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.76
Residue 65: the j domain

Full DNAJA4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAJA4 p.Ala25Val Uncertain significance ★ ⚠ same type
DNAJA4 p.Ala314Val Uncertain significance ★ ⚠ same type
DNAJA4 p.Arg157Trp Uncertain significance ★ ⚠ same type
DNAJA4 p.Arg187Cys Uncertain significance ★ ⚠ same type
DNAJA4 p.Arg193Leu Uncertain significance ★ ⚠ same type
DNAJA4 p.Arg255Gln Uncertain significance ★ ⚠ same type
DNAJA4 p.Arg305Cys Uncertain significance ★ ⚠ same type
DNAJA4 p.Arg350Gly 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/dnaja4-p-asp65his (accessed [today's date]).

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