Is DPM2 p.Tyr49Cys (c.146A>G) pathogenic?

DPM2 p.Tyr49Cys (c.146A>G) is classified Uncertain significance in DPM2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-19). AlphaMissense: likely benign (0.2747); Very rare (popmax 0.00385%, nfe); Associated with congenital muscular dystrophy with intellectual disability and severe epilepsy.

How common is DPM2 p.Tyr49Cys (c.146A>G) in the general population?

DPM2 p.Tyr49Cys (c.146A>G) is very rare (popmax 0.00385%, nfe) (gnomAD).

What do computational predictors say about DPM2 p.Tyr49Cys (c.146A>G)?

AlphaMissense predicts likely benign (score 0.2747) — an in-silico prediction, not a clinical call.

DPM2 p.Tyr49Cys

Q: What condition is associated with DPM2 p.Tyr49Cys (c.146A>G)?

DPM2 p.Tyr49Cys (c.146A>G) is associated with congenital muscular dystrophy with intellectual disability and severe epilepsy (ClinVar).

Q: How is Congenital muscular dystrophy with intellectual disability and severe epilepsy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.146A>G · rs779093563 · VCV568680

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00385%, nfe)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital muscular dystrophy with intellectual disability and severe epilepsy

Computational evidence

Protein change
AlphaMissense	0.2747	likely benign
REVEL	0.816	moderately pathogenic-leaning
SaProt	LLR -11.43	damaging
⇒ REVEL and SaProt call this damaging; AlphaMissense does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 2,095 bp · p 0.35 · 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.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00385% European (non-Finnish) · 44/1,143,264 alleles

Filtering AF 0.00292% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0026%

Overall 0.00305% 47/1,543,194 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00385%	25,983
Remaining individualsnot grpmax-eligible	0.00337%	29,706
Finnishnot grpmax-eligible	0.00162%	61,908

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: DPM2
Protein: p.Tyr49Cys
Coding: c.146A>G
MANE Select: NM_003863
dbSNP: rs779093563
Type: single nucleotide variant
Location: chr9:127936603 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.96

Full DPM2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital muscular dystrophy with intellectual disability and severe epilepsy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Congenital muscular dystrophy with intellectual disability and severe epilepsy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

DPM2 p.Tyr49Ter Pathogenic ★ same residue
DPM2 p.Tyr49Asn Uncertain significance ★ ⚠ same residue
DPM2 p.Arg47Ter Pathogenic/Likely pathogenic ★★ same condition
DPM2 p.Ala52Thr Uncertain significance ★★ ⚠ same condition
DPM2 p.Leu30Val Uncertain significance ★★ ⚠ same condition
DPM2 p.Leu62Val Uncertain significance ★★ ⚠ same condition
DPM2 p.Tyr43His Uncertain significance ★★ ⚠ same condition
DPM2 p.Val51Ile 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/dpm2-p-tyr49cys (accessed [today's date]).

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