Is DYM p.Thr255Ile (c.764C>T) pathogenic?

DYM p.Thr255Ile (c.764C>T) is classified Uncertain significance in DYM (ClinVar, Single submitter, 1 submitter; last evaluated 2023-07-07). AlphaMissense: likely pathogenic (0.8698); Very rare (popmax 0.00133%, afr).

How common is DYM p.Thr255Ile (c.764C>T) in the general population?

DYM p.Thr255Ile (c.764C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about DYM p.Thr255Ile (c.764C>T)?

AlphaMissense predicts likely pathogenic (score 0.8698) — an in-silico prediction, not a clinical call.

DYM p.Thr255Ile

c.764C>T · rs1216551325 · VCV1922468

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8698 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.8698	likely pathogenic
REVEL	0.5	indeterminate
SaProt	LLR -11.42	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>C here scores Δ0.70 · evaluated, not missing
Constraint at this position
Conservation	phyloP 9.9	GERP 2.4, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 158 kb · p 0.51 · regional, not allelic
Overall
CADD	24.5	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 0.00133% African / African-American · 1/75,022 alleles

Overall 6.84e-05% 1/1,461,382 alleles · very rare

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.Thr255Ile
Coding: c.764C>T
MANE Select: NM_001353214
dbSNP: rs1216551325
Type: single nucleotide variant
Location: chr18:49286616 (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 p.Thr255fs Pathogenic same residue
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

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-thr255ile (accessed [today's date]).

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