Is POMT2 p.Arg421Gln (c.1262G>A) pathogenic?

POMT2 p.Arg421Gln (c.1262G>A) is classified Conflicting classifications of pathogenicity in POMT2 (ClinVar, Conflicting submitters, 9 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.3278); Low-frequency (popmax 1.13%, afr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2N.

How common is POMT2 p.Arg421Gln (c.1262G>A) in the general population?

POMT2 p.Arg421Gln (c.1262G>A) is low-frequency (popmax 1.13%, afr) (gnomAD).

How is POMT2-related limb-girdle muscular dystrophy R14 inherited?

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

What do computational predictors say about POMT2 p.Arg421Gln (c.1262G>A)?

AlphaMissense predicts likely benign (score 0.3278) — an in-silico prediction, not a clinical call.

POMT2 p.Arg421Gln

Q: What condition is associated with POMT2 p.Arg421Gln (c.1262G>A)?

POMT2 p.Arg421Gln (c.1262G>A) is associated with autosomal recessive limb-girdle muscular dystrophy type 2N, muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2, muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2 (ClinVar).

c.1262G>A · rs151078549 · VCV194086

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 9 submitters

AlphaMissense

likely benign

0.3278 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.13%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2N

Computational evidence

Protein change
AlphaMissense	0.3278	likely benign
REVEL	0.808	moderately pathogenic-leaning
SaProt	LLR -8.12	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.7, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 43 kb · p 0.62 · regional, not allelic
Overall
CADD	31.0	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 1.13% African / African-American · 847/74,980 alleles

Filtering AF 1.07% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.04%

Overall 0.0615% 993/1,614,036 alleles · low-frequency exomes 529/1,461,870 · genomes 464/152,166 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	1.13%	89
Admixed American	0.102%	984
Remaining individualsnot grpmax-eligible	0.0736%	1,359
Middle Eastern	0.0165%	6,062
East Asian	0.0111%	8,978
South Asian	0.00878%	11,384
European (non-Finnish)	0.00212%	47,201

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: POMT2
Protein: p.Arg421Gln
Coding: c.1262G>A
MANE Select: NM_013382
dbSNP: rs151078549
Type: single nucleotide variant
Location: chr14:77286814 (GRCh38)
Gene constraint: LOEUF 0.944 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.96
Residue 421: the mir 2 domain

Full POMT2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

autosomal recessive limb-girdle muscular dystrophy type 2N — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A2 muscular dystrophy-dystroglycanopathy (congenital with intellectual disability), type B2

For POMT2-related limb-girdle muscular dystrophy R14 (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy
Prevalence: <1 / 1 000 000 (Worldwide)

Similar variants

POMT2 p.Arg421Trp Pathogenic/Likely pathogenic ★★ same residue
POMT2 p.Arg421= Likely benign ★ same residue
POMT2 p.Arg421fs Pathogenic same residue
POMT2 c.1006+1G>A Pathogenic ★★ same condition
POMT2 c.1184-1G>C Likely pathogenic ★★ same condition
POMT2 c.1254-2A>G Likely pathogenic ★★ same condition
POMT2 c.1333-14G>A Pathogenic/Likely pathogenic ★★ same condition
POMT2 c.1786-2A>T Pathogenic/Likely pathogenic ★★ 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/pomt2-p-arg421gln (accessed [today's date]).

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