Is DPM2 p.Thr76Ser (c.227C>G) pathogenic?

DPM2 p.Thr76Ser (c.227C>G) is classified Benign in DPM2 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-02-04). AlphaMissense: likely benign (0.0523); Common (popmax 87.3%, nfe) — too common for a highly-penetrant pathogenic allele; Associated with congenital muscular dystrophy with intellectual disability and severe epilepsy.

What do computational predictors say about DPM2 p.Thr76Ser (c.227C>G)?

AlphaMissense predicts likely benign (score 0.0523) — an in-silico prediction, not a clinical call.

DPM2 p.Thr76Ser

Q: What condition is associated with DPM2 p.Thr76Ser (c.227C>G)?

DPM2 p.Thr76Ser (c.227C>G) is associated with congenital muscular dystrophy with intellectual disability and severe epilepsy (ClinVar).

Q: How common is DPM2 p.Thr76Ser (c.227C>G) in the general population?

DPM2 p.Thr76Ser (c.227C>G) is common (popmax 87.3%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

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.227C>G · rs7997 · VCV128921

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.0523 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 87.3%, nfe) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

congenital muscular dystrophy with intellectual disability and severe epilepsy

Computational evidence

Protein change
AlphaMissense	0.0523	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -5.50	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.1	GERP -3.3, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 2,095 bp · p 0.35 · regional, not allelic
Overall
CADD	0.862	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 87.3% European (non-Finnish) · 1,028,138/1,177,306 alleles

Filtering AF 87.2% ClinGen BA1/BS1 input FAF95, joint · FAF99 87.1%

Overall 83.4% 1,343,159/1,610,654 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	91.9%	1
European (non-Finnish)grpmax	87.3%	1
Finnishnot grpmax-eligible	86.8%	1
Admixed American	81.6%	1
Remaining individualsnot grpmax-eligible	80.8%	1
Middle Eastern	74.2%	1
Ashkenazi Jewishnot grpmax-eligible	72.6%	1
South Asian	70.4%	1
African / African-American	67.3%	1
East Asian	42.5%	2

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Thr76Ser
Coding: c.227C>G
MANE Select: NM_003863
dbSNP: rs7997
Type: single nucleotide variant
Location: chr9:127935750 (GRCh38)
Gene constraint: LOEUF 1.274 · pLI 0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.96
Residue 76: a UniProt-annotated variant site (in)

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.Thr76Ala 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
DPM2 c.3+12A>G Benign/Likely benign ★★ 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-thr76ser (accessed [today's date]).

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