Is DYM p.Val376Leu (c.1126G>C) pathogenic?

DYM p.Val376Leu (c.1126G>C) is classified Uncertain significance in DYM (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-11). AlphaMissense: ambiguous (0.5034); Ultra-rare (popmax 0.0226%, eas); Associated with Inborn genetic diseases.

What condition is associated with DYM p.Val376Leu (c.1126G>C)?

DYM p.Val376Leu (c.1126G>C) is associated with Inborn genetic diseases (ClinVar).

How common is DYM p.Val376Leu (c.1126G>C) in the general population?

DYM p.Val376Leu (c.1126G>C) is ultra-rare (popmax 0.0226%, eas) (gnomAD).

What do computational predictors say about DYM p.Val376Leu (c.1126G>C)?

AlphaMissense predicts ambiguous (score 0.5034) — an in-silico prediction, not a clinical call.

DYM p.Val376Leu

c.1126G>C · VCV3274132

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5034 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0226%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5034	ambiguous
REVEL	0.766	pathogenic-leaning
SaProt	LLR -7.71	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 7.6	GERP 2, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 158 kb · p 0.51 · regional, not allelic
Overall
CADD	28.5	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 0.0226% East Asian · 10/44,254 alleles

Filtering AF 0.0122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00928%

Overall 0.000722% 11/1,522,686 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0226%	4,425
European (non-Finnish)	9.11e-05%	1,098,276

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.Val376Leu
Coding: c.1126G>C
MANE Select: NM_001353214
Type: single nucleotide variant
Location: chr18:49272303 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

DYM p.Tyr132Ter Pathogenic/Likely pathogenic ★★ same condition
DYM p.Ala254Ser Uncertain significance ★★ ⚠ same condition
DYM p.Ala270Val Uncertain significance ★★ ⚠ same condition
DYM p.Ala300Val Uncertain significance ★★ ⚠ same condition
DYM p.Ala327Asp Uncertain significance ★★ ⚠ same condition
DYM p.Ala668Val Uncertain significance ★★ ⚠ same condition
DYM p.Arg475His Uncertain significance ★★ ⚠ same condition
DYM p.Arg673Gly 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/dym-p-val376leu (accessed [today's date]).

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