Is DNAJC6 p.Arg225Trp (c.673C>T) pathogenic?

DNAJC6 p.Arg225Trp (c.673C>T) is classified Uncertain significance in DNAJC6 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-10). AlphaMissense: ambiguous (0.3891); Very rare (popmax 0.00427%, afr).

How common is DNAJC6 p.Arg225Trp (c.673C>T) in the general population?

DNAJC6 p.Arg225Trp (c.673C>T) is very rare (popmax 0.00427%, afr) (gnomAD).

What do computational predictors say about DNAJC6 p.Arg225Trp (c.673C>T)?

AlphaMissense predicts ambiguous (score 0.3891) — an in-silico prediction, not a clinical call.

DNAJC6 p.Arg225Trp

c.673C>T · rs762184162 · VCV2683718

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3891 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00427%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3891	ambiguous
REVEL	0.766	pathogenic-leaning
SaProt	LLR -9.86	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.9	GERP 6.5, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 103 kb · p 3.7e-07 · regional, not allelic
Overall
CADD	26.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM R168W vs ClinVar R225W) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00427% African / African-American · 3/70,176 alleles

Filtering AF 0.0016% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00136%

Overall 0.00211% 32/1,513,096 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00427%	23,392
South Asian	0.0027%	37,012
East Asian	0.00259%	38,590
European (non-Finnish)	0.0023%	43,559

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: DNAJC6
Protein: p.Arg225Trp
Coding: c.673C>T
MANE Select: NM_001256864
dbSNP: rs762184162
Type: single nucleotide variant
Location: chr1:65384199 (GRCh38)
Gene constraint: LOEUF 0.416 · pLI 1.00 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 64.29

Full DNAJC6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAJC6 p.Arg225Gln Uncertain significance ★ ⚠ same residue
DNAJC6 p.Arg330Ter Pathogenic ★★ same type
DNAJC6 p.Ala226Val Uncertain significance ★★ ⚠ same type
DNAJC6 p.Ala234Thr Uncertain significance ★★ ⚠ same type
DNAJC6 p.Ala277Thr Uncertain significance ★★ ⚠ same type
DNAJC6 p.Ala611Val Uncertain significance ★★ ⚠ same type
DNAJC6 p.Ala626Val Uncertain significance ★★ ⚠ same type
DNAJC6 p.Ala770Val 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/dnajc6-p-arg225trp (accessed [today's date]).

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