Is DNAJA4 p.Ala25Val (c.74C>T) pathogenic?

DNAJA4 p.Ala25Val (c.74C>T) is classified Uncertain significance in DNAJA4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: likely pathogenic (0.7668); Very rare (popmax 0.00401%, afr).

How common is DNAJA4 p.Ala25Val (c.74C>T) in the general population?

DNAJA4 p.Ala25Val (c.74C>T) is very rare (popmax 0.00401%, afr) (gnomAD).

What do computational predictors say about DNAJA4 p.Ala25Val (c.74C>T)?

AlphaMissense predicts likely pathogenic (score 0.7668) — an in-silico prediction, not a clinical call.

DNAJA4 p.Ala25Val

c.74C>T · VCV4013487

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7668 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00401%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7668	likely pathogenic
REVEL	0.319	indeterminate
SaProt	LLR -11.15	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1.8, phastCons 1
Regional constraint	o/e 0.87	unconstrained · MANE · 16 kb · p 0.0033 · regional, not allelic
Overall
CADD	26.7	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 0.00401% African / African-American · 3/74,738 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000186% 3/1,610,512 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.Ala25Val
Coding: c.74C>T
MANE Select: NM_001130182
Type: single nucleotide variant
Location: chr15:78264837 (GRCh38)
Gene constraint: LOEUF 1.024 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.76
Residue 25: the j domain

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

Similar variants

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
DNAJA4 p.Arg350Pro 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-ala25val (accessed [today's date]).

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