Is DNAJC19 p.Ile66Met (c.198A>G) pathogenic?

DNAJC19 p.Ile66Met (c.198A>G) is classified Uncertain significance in DNAJC19 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-05). AlphaMissense: likely pathogenic (0.9313); Very rare (popmax 0.00254%, nfe); Associated with Inborn genetic diseases.

What condition is associated with DNAJC19 p.Ile66Met (c.198A>G)?

DNAJC19 p.Ile66Met (c.198A>G) is associated with Inborn genetic diseases, 3-methylglutaconic aciduria type 5 (ClinVar).

How common is DNAJC19 p.Ile66Met (c.198A>G) in the general population?

DNAJC19 p.Ile66Met (c.198A>G) is very rare (popmax 0.00254%, nfe) (gnomAD).

What do computational predictors say about DNAJC19 p.Ile66Met (c.198A>G)?

AlphaMissense predicts likely pathogenic (score 0.9313) — an in-silico prediction, not a clinical call.

DNAJC19 p.Ile66Met

c.198A>G · rs1714941468 · VCV2024044

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.9313 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00254%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9313	likely pathogenic
REVEL	0.389	indeterminate
SaProt	LLR -11.83	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 2.3	GERP -2.5, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 4,959 bp · p 0.0025 · regional, not allelic
Overall
CADD	23.6	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 0.00254% European (non-Finnish) · 30/1,179,560 alleles

Filtering AF 0.0018% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00157%

Overall 0.00212% 31/1,461,276 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00254%	39,319
African / African-American	0.00133%	75,034

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: DNAJC19
Protein: p.Ile66Met
Coding: c.198A>G
MANE Select: NM_145261
dbSNP: rs1714941468
Type: single nucleotide variant
Location: chr3:180986954 (GRCh38)
Gene constraint: LOEUF 1.547 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.50
Residue 66: the j domain

Full DNAJC19 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: 3-methylglutaconic aciduria type 5

Similar variants

DNAJC19 c.130-1G>C Pathogenic ★★ same condition
DNAJC19 c.4-1G>A Likely pathogenic ★★ same condition
DNAJC19 c.55+1G>A Pathogenic/Likely pathogenic ★★ same condition
DNAJC19 p.Ala25Thr Uncertain significance ★★ ⚠ same condition
DNAJC19 p.Ala73Thr Uncertain significance ★★ same condition
DNAJC19 p.Arg20Cys Uncertain significance ★★ ⚠ same condition
DNAJC19 p.Arg84Gln Uncertain significance ★★ ⚠ same condition
DNAJC19 p.Gly68Asp Uncertain significance ★★ ⚠ same condition

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/dnajc19-p-ile66met (accessed [today's date]).

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