Is DYM p.His478Arg (c.1433A>G) pathogenic?

DYM p.His478Arg (c.1433A>G) is classified Uncertain significance in DYM (ClinVar, Single submitter, 1 submitter; last evaluated 2021-08-05). AlphaMissense: likely pathogenic (0.9915); Very rare (popmax 0.0017%, nfe).

How common is DYM p.His478Arg (c.1433A>G) in the general population?

DYM p.His478Arg (c.1433A>G) is very rare (popmax 0.0017%, nfe) (gnomAD).

What do computational predictors say about DYM p.His478Arg (c.1433A>G)?

AlphaMissense predicts likely pathogenic (score 0.9915) — an in-silico prediction, not a clinical call.

DYM p.His478Arg

c.1433A>G · rs376581531 · VCV1372699

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9915 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0017%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9915	likely pathogenic · top 6% in DYM
REVEL	0.935	strongly pathogenic-leaning
SaProt	LLR -13.10	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.9	GERP 7, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 154 kb · p 7.5e-06 · regional, not allelic
Overall
CADD	26.8	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 0.0017% European (non-Finnish) · 20/1,179,860 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.0013% 21/1,613,816 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0017%	58,993
Remaining individualsnot grpmax-eligible	0.0016%	62,468

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: DYM
Protein: p.His478Arg
Coding: c.1433A>G
MANE Select: NM_001353214
dbSNP: rs376581531
Type: single nucleotide variant
Location: chr18:49257037 (GRCh38)
Gene constraint: LOEUF 1.081 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 87.91

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

Similar variants

DYM c.1728+2T>C Pathogenic/Likely pathogenic ★★ same type
DYM c.947-2A>G Pathogenic/Likely pathogenic ★★ same type
DYM p.Arg204Ter Pathogenic ★★ same type
DYM p.Arg428Ter Pathogenic/Likely pathogenic ★★ same type
DYM p.Arg588Ter Pathogenic ★★ same type
DYM p.Arg70Ter Pathogenic/Likely pathogenic ★★ same type
DYM p.Gln306Ter Pathogenic/Likely pathogenic ★★ same type
DYM p.Glu87Lys Pathogenic ★★ 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/dym-p-his478arg (accessed [today's date]).

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