Is DNAJC5B p.Ile64Ser (c.191T>G) pathogenic?

DNAJC5B p.Ile64Ser (c.191T>G) is classified Uncertain significance in DNAJC5B (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-31). AlphaMissense: likely pathogenic (0.9745); Ultra-rare (popmax 0.0667%, amr).

How common is DNAJC5B p.Ile64Ser (c.191T>G) in the general population?

DNAJC5B p.Ile64Ser (c.191T>G) is ultra-rare (popmax 0.0667%, amr) (gnomAD).

What do computational predictors say about DNAJC5B p.Ile64Ser (c.191T>G)?

AlphaMissense predicts likely pathogenic (score 0.9745) — an in-silico prediction, not a clinical call.

DNAJC5B p.Ile64Ser

c.191T>G · VCV4243314

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9745 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0667%, amr)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9745	likely pathogenic · top 4% in DNAJC5B
REVEL	0.815	moderately pathogenic-leaning
SaProt	LLR -15.85	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 7.9	GERP 2.5, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 48 kb · p 0.85 · regional, not allelic
Overall
CADD	28.6	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 0.0667% Admixed American · 40/59,992 alleles

Filtering AF 0.0503% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0446%

Overall 0.00297% 48/1,613,942 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0667%	1,500
Remaining individualsnot grpmax-eligible	0.0016%	62,486
European (non-Finnish)	0.000593%	168,574

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: DNAJC5B
Protein: p.Ile64Ser
Coding: c.191T>G
MANE Select: NM_033105
Type: single nucleotide variant
Location: chr8:66076731 (GRCh38)
Gene constraint: LOEUF 1.356 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 74.07
Residue 64: the j domain

Full DNAJC5B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAJC5B p.Ala19Val Uncertain significance ★ ⚠ same type
DNAJC5B p.Arg11Trp Uncertain significance ★ ⚠ same type
DNAJC5B p.Cys127Ser Uncertain significance ★ ⚠ same type
DNAJC5B p.Glu143Ter Uncertain significance ★ same type
DNAJC5B p.Glu160Asp Uncertain significance ★ ⚠ same type
DNAJC5B p.Gly118Val Uncertain significance ★ ⚠ same type
DNAJC5B p.Gly87Val Uncertain significance ★ ⚠ same type
DNAJC5B p.Ile5Met 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/dnajc5b-p-ile64ser (accessed [today's date]).

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