Is DNAJC3 p.Pro423Ser (c.1267C>T) pathogenic?

DNAJC3 p.Pro423Ser (c.1267C>T) is classified Uncertain significance in DNAJC3 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-05-04). AlphaMissense: likely pathogenic (0.9968); Absent from gnomAD v4.1.

How common is DNAJC3 p.Pro423Ser (c.1267C>T) in the general population?

DNAJC3 p.Pro423Ser (c.1267C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about DNAJC3 p.Pro423Ser (c.1267C>T)?

AlphaMissense predicts likely pathogenic (score 0.9968) — an in-silico prediction, not a clinical call.

DNAJC3 p.Pro423Ser

c.1267C>T · rs2139698639 · VCV1684693

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9968 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9968	likely pathogenic · top 3% in DNAJC3
REVEL	0.523	indeterminate
SaProt	LLR -14.60	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 7.6	GERP 1.1, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 114 kb · p 0.0067 · regional, not allelic
Overall
CADD	31.0	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: DNAJC3
Protein: p.Pro423Ser
Coding: c.1267C>T
MANE Select: NM_006260
dbSNP: rs2139698639
Type: single nucleotide variant
Location: chr13:95787065 (GRCh38)
Gene constraint: LOEUF 0.738 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 86.78 · 2 PDB
Residue 423: the j domain; an α-helix

Full DNAJC3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAJC3 p.Arg393Ter Pathogenic/Likely pathogenic ★★ same type
DNAJC3 p.Asp69Gly Uncertain significance ★★ ⚠ same type
DNAJC3 p.Leu231Val Uncertain significance ★★ ⚠ same type
DNAJC3 p.Ser450Cys Uncertain significance ★★ ⚠ same type
DNAJC3 p.Thr171Ile Uncertain significance ★★ ⚠ same type
DNAJC3 c.848+10T>C Benign ★★ same type
DNAJC3 p.Ala54= Benign/Likely benign ★★ same type
DNAJC3 p.Gln99= Likely benign ★★ 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/dnajc3-p-pro423ser (accessed [today's date]).

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