Is DNAJC2 p.Ser490Tyr (c.1469C>A) pathogenic?

DNAJC2 p.Ser490Tyr (c.1469C>A) is classified Uncertain significance in DNAJC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: likely benign (0.3234); Very rare (popmax 0.00358%, nfe).

How common is DNAJC2 p.Ser490Tyr (c.1469C>A) in the general population?

DNAJC2 p.Ser490Tyr (c.1469C>A) is very rare (popmax 0.00358%, nfe) (gnomAD).

What do computational predictors say about DNAJC2 p.Ser490Tyr (c.1469C>A)?

AlphaMissense predicts likely benign (score 0.3234) — an in-silico prediction, not a clinical call.

DNAJC2 p.Ser490Tyr

c.1469C>A · VCV4013646

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3234 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00358%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3234	likely benign
REVEL	0.231	benign-leaning
SaProt	LLR -10.88	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	GERP 0.91, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 7,271 bp · p 0.069 · regional, not allelic
Overall
CADD	26.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00358% European (non-Finnish) · 42/1,174,330 alleles

Filtering AF 0.00268% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00237%

Overall 0.00275% 44/1,601,130 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00358%	27,960
Remaining individualsnot grpmax-eligible	0.00162%	61,908
African / African-American	0.00135%	74,278

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: DNAJC2
Protein: p.Ser490Tyr
Coding: c.1469C>A
MANE Select: NM_014377
Type: single nucleotide variant
Location: chr7:103316047 (GRCh38)
Gene constraint: LOEUF 0.466 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 85.51 · 2 PDB
Residue 490: the sant 1 domain

Full DNAJC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAJC2 p.Ser490Cys Uncertain significance ★ ⚠ same residue
DNAJC2 c.331+1G>A Uncertain significance ★ same type
DNAJC2 p.Ala308Thr Uncertain significance ★ ⚠ same type
DNAJC2 p.Ala436Gly Uncertain significance ★ ⚠ same type
DNAJC2 p.Ala48Thr Uncertain significance ★ ⚠ same type
DNAJC2 p.Ala616Thr Uncertain significance ★ ⚠ same type
DNAJC2 p.Arg105Gly Uncertain significance ★ ⚠ same type
DNAJC2 p.Arg303Gln 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/dnajc2-p-ser490tyr (accessed [today's date]).

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