Is DNAJC4 p.Arg92Cys (c.274C>T) pathogenic?

DNAJC4 p.Arg92Cys (c.274C>T) is classified Uncertain significance in DNAJC4 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: likely pathogenic (0.6512); Ultra-rare (popmax 0.0147%, afr).

How common is DNAJC4 p.Arg92Cys (c.274C>T) in the general population?

DNAJC4 p.Arg92Cys (c.274C>T) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about DNAJC4 p.Arg92Cys (c.274C>T)?

AlphaMissense predicts likely pathogenic (score 0.6512) — an in-silico prediction, not a clinical call.

DNAJC4 p.Arg92Cys

c.274C>T · VCV4243301

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6512 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6512	likely pathogenic
REVEL	0.766	pathogenic-leaning
SaProt	LLR -13.25	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 7.6	GERP 0.51, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 3,326 bp · p 0.24 · regional, not allelic
Overall
CADD	28.8	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 0.0147% African / African-American · 11/74,856 alleles

Filtering AF 0.00816% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00634%

Overall 0.00174% 28/1,613,266 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0147%	6,805
Finnishnot grpmax-eligible	0.00938%	10,666
Remaining individualsnot grpmax-eligible	0.0048%	20,813
South Asian	0.0033%	30,344
European (non-Finnish)	0.000424%	235,906

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: DNAJC4
Protein: p.Arg92Cys
Coding: c.274C>T
MANE Select: NM_005528
Type: single nucleotide variant
Location: chr11:64232523 (GRCh38)
Gene constraint: LOEUF 1.444 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.83
Residue 92: the j domain; the 'disordered' region

Full DNAJC4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAJC4 p.Arg92His Uncertain significance ★ ⚠ same residue
DNAJC4 p.Ala200Asp Uncertain significance ★ ⚠ same type
DNAJC4 p.Ala204Pro Uncertain significance ★ ⚠ same type
DNAJC4 p.Ala26Thr Uncertain significance ★ ⚠ same type
DNAJC4 p.Arg100Cys Uncertain significance ★ ⚠ same type
DNAJC4 p.Arg100His Uncertain significance ★ ⚠ same type
DNAJC4 p.Arg109Pro Uncertain significance ★ ⚠ same type
DNAJC4 p.Arg15Gly 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/dnajc4-p-arg92cys (accessed [today's date]).

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