Is DNAJA2 p.Leu74Val (c.220C>G) pathogenic?

DNAJA2 p.Leu74Val (c.220C>G) is classified Uncertain significance in DNAJA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-09). AlphaMissense: ambiguous (0.5176); Ultra-rare (popmax 0.0495%, mid).

How common is DNAJA2 p.Leu74Val (c.220C>G) in the general population?

DNAJA2 p.Leu74Val (c.220C>G) is ultra-rare (popmax 0.0495%, mid) (gnomAD).

What do computational predictors say about DNAJA2 p.Leu74Val (c.220C>G)?

AlphaMissense predicts ambiguous (score 0.5176) — an in-silico prediction, not a clinical call.

DNAJA2 p.Leu74Val

c.220C>G · VCV4243005

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5176 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0495%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5176	ambiguous
REVEL	0.071	moderately benign-leaning
SaProt	LLR -7.91	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.35 · evaluated, not missing
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.67	unconstrained · MANE · 17 kb · p 8e-14 · regional, not allelic
Overall
CADD	23.4	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 0.0495% Middle Eastern · 3/6,058 alleles

Filtering AF 0.0134% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00718%

Overall 0.000547% 8/1,461,674 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0495%	2,019
Admixed American	0.00334%	29,973
Remaining individualsnot grpmax-eligible	0.0032%	31,247
African / African-American	0.00133%	74,978

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: DNAJA2
Protein: p.Leu74Val
Coding: c.220C>G
MANE Select: NM_005880
Type: single nucleotide variant
Location: chr16:46971491 (GRCh38)
Gene constraint: LOEUF 0.258 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 84.10 · 1 PDB

Full DNAJA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

DNAJA2 p.Gly79Ser Uncertain significance ★★ ⚠ same type
DNAJA2 p.Arg107Gln Uncertain significance ★ ⚠ same type
DNAJA2 p.Arg110Gly Uncertain significance ★ ⚠ same type
DNAJA2 p.Arg112Gly Uncertain significance ★ ⚠ same type
DNAJA2 p.Arg165Gln Uncertain significance ★ ⚠ same type
DNAJA2 p.Arg201Ser Uncertain significance ★ ⚠ same type
DNAJA2 p.Arg388His Uncertain significance ★ ⚠ same type
DNAJA2 p.Arg68Lys 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/dnaja2-p-leu74val (accessed [today's date]).

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