Is DNAJC19 p.Arg20His (c.59G>A) pathogenic?

DNAJC19 p.Arg20His (c.59G>A) is classified Conflicting classifications of pathogenicity in DNAJC19 (ClinVar, Conflicting submitters, 3 submitters; last evaluated 2024-10-18). AlphaMissense: ambiguous (0.5399); Ultra-rare (popmax 0.0329%, sas); Associated with 3-methylglutaconic aciduria type 5.

What condition is associated with DNAJC19 p.Arg20His (c.59G>A)?

DNAJC19 p.Arg20His (c.59G>A) is associated with 3-methylglutaconic aciduria type 5 (ClinVar).

How common is DNAJC19 p.Arg20His (c.59G>A) in the general population?

DNAJC19 p.Arg20His (c.59G>A) is ultra-rare (popmax 0.0329%, sas) (gnomAD).

How is Dilated cardiomyopathy with ataxia inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about DNAJC19 p.Arg20His (c.59G>A)?

AlphaMissense predicts ambiguous (score 0.5399) — an in-silico prediction, not a clinical call.

DNAJC19 p.Arg20His

c.59G>A · rs756192515 · VCV466328

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.5399 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0329%, sas)

Conditions

3-methylglutaconic aciduria type 5

Computational evidence

Protein change
AlphaMissense	0.5399	ambiguous
REVEL	0.588	indeterminate
SaProt	LLR -12.50	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 4,959 bp · p 0.0025 · regional, not allelic
Overall
CADD	24.5	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 0.0329% South Asian · 30/91,088 alleles

Filtering AF 0.0237% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0205%

Overall 0.0044% 71/1,614,008 alleles · ultra-rare exomes 66/1,461,876 · genomes 5/152,132 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0329%	3,036
African / African-American	0.00935%	10,701
European (non-Finnish)	0.00288%	34,707

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.Arg20His
Coding: c.59G>A
MANE Select: NM_145261
dbSNP: rs756192515
Type: single nucleotide variant
Location: chr3:180988093 (GRCh38)
Gene constraint: LOEUF 1.547 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.50

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

Disease context

3-methylglutaconic aciduria type 5 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Dilated cardiomyopathy with ataxia (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood, Infancy

Similar variants

DNAJC19 p.Arg20_Tyr21insTer Pathogenic/Likely pathogenic ★★ same residue
DNAJC19 p.Arg20Cys Uncertain significance ★★ ⚠ same residue
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.Arg84Gln 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-arg20his (accessed [today's date]).

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