Is DNAJC8 p.Pro49Ala (c.145C>G) pathogenic?

DNAJC8 p.Pro49Ala (c.145C>G) is classified Uncertain significance in DNAJC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-19). AlphaMissense: ambiguous (0.3881); Ultra-rare (popmax 0.015%, amr).

How common is DNAJC8 p.Pro49Ala (c.145C>G) in the general population?

DNAJC8 p.Pro49Ala (c.145C>G) is ultra-rare (popmax 0.015%, amr) (gnomAD).

What do computational predictors say about DNAJC8 p.Pro49Ala (c.145C>G)?

AlphaMissense predicts ambiguous (score 0.3881) — an in-silico prediction, not a clinical call.

DNAJC8 p.Pro49Ala

c.145C>G · VCV3504050

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3881 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.015%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3881	ambiguous
REVEL	0.289	benign-leaning
SaProt	LLR -7.87	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.59	unconstrained · MANE · 32 kb · p 3.2e-11 · regional, not allelic
Overall
CADD	24.7	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 0.015% Admixed American · 9/60,000 alleles

Filtering AF 0.00773% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00579%

Overall 0.00124% 20/1,613,236 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.015%	6,667
South Asian	0.0022%	45,522
European (non-Finnish)	0.000763%	131,110

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: DNAJC8
Protein: p.Pro49Ala
Coding: c.145C>G
MANE Select: NM_014280
Type: single nucleotide variant
Location: chr1:28228957 (GRCh38)
Gene constraint: LOEUF 0.733 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.60 · 1 PDB

Full DNAJC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAJC8 p.Ala161Thr Uncertain significance ★ ⚠ same type
DNAJC8 p.Ala93Val Uncertain significance ★ ⚠ same type
DNAJC8 p.Arg95Gly Uncertain significance ★ ⚠ same type
DNAJC8 p.Asn55Ser Uncertain significance ★ ⚠ same type
DNAJC8 p.Asp92Val Uncertain significance ★ ⚠ same type
DNAJC8 p.Glu179Asp Uncertain significance ★ ⚠ same type
DNAJC8 p.Glu67Lys Uncertain significance ★ ⚠ same type
DNAJC8 p.Gly11Asp 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/dnajc8-p-pro49ala (accessed [today's date]).

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