Is DNAJC1 p.Cys526Phe (c.1577G>T) pathogenic?

DNAJC1 p.Cys526Phe (c.1577G>T) is classified Uncertain significance in DNAJC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-29). AlphaMissense: likely benign (0.1447); Ultra-rare (popmax 0.0135%, nfe).

How common is DNAJC1 p.Cys526Phe (c.1577G>T) in the general population?

DNAJC1 p.Cys526Phe (c.1577G>T) is ultra-rare (popmax 0.0135%, nfe) (gnomAD).

What do computational predictors say about DNAJC1 p.Cys526Phe (c.1577G>T)?

AlphaMissense predicts likely benign (score 0.1447) — an in-silico prediction, not a clinical call.

DNAJC1 p.Cys526Phe

c.1577G>T · VCV4243104

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1447 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0135%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1447	likely benign
REVEL	0.138	moderately benign-leaning
SaProt	LLR -7.97	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 5.9	GERP 1.4, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 247 kb · p 0.65 · regional, not allelic
Overall
CADD	23.7	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 0.0135% European (non-Finnish) · 159/1,179,954 alleles

Filtering AF 0.0117% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0111%

Overall 0.0104% 168/1,613,904 alleles · ultra-rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0135%	7,421
Admixed American	0.00667%	14,995
Remaining individualsnot grpmax-eligible	0.0064%	15,619
Finnishnot grpmax-eligible	0.00156%	64,044

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: DNAJC1
Protein: p.Cys526Phe
Coding: c.1577G>T
MANE Select: NM_022365
Type: single nucleotide variant
Location: chr10:21759189 (GRCh38)
Gene constraint: LOEUF 0.961 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 71.45 · 2 PDB
Residue 526: an α-helix; the sant 2 domain

Full DNAJC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAJC1 p.Ala263Ser Uncertain significance ★ ⚠ same type
DNAJC1 p.Ala3Thr Uncertain significance ★ ⚠ same type
DNAJC1 p.Ala417Gly Uncertain significance ★ ⚠ same type
DNAJC1 p.Ala455Val Uncertain significance ★ ⚠ same type
DNAJC1 p.Ala490Gly Uncertain significance ★ ⚠ same type
DNAJC1 p.Ala524Ser Uncertain significance ★ ⚠ same type
DNAJC1 p.Ala537Thr Uncertain significance ★ ⚠ same type
DNAJC1 p.Arg107Thr 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/dnajc1-p-cys526phe (accessed [today's date]).

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