Is PLEC p.Pro4273Ser (c.12817C>T) pathogenic?

PLEC p.Pro4273Ser (c.12817C>T) is classified Benign/Likely benign in PLEC (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-26). AlphaMissense: likely benign (0.298); Rare (popmax 0.477%, afr); Associated with autosomal recessive limb-girdle muscular dystrophy type 2Q.

What condition is associated with PLEC p.Pro4273Ser (c.12817C>T)?

PLEC p.Pro4273Ser (c.12817C>T) is associated with autosomal recessive limb-girdle muscular dystrophy type 2Q, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Pro4273Ser (c.12817C>T) in the general population?

PLEC p.Pro4273Ser (c.12817C>T) is rare (popmax 0.477%, afr) (gnomAD).

What do computational predictors say about PLEC p.Pro4273Ser (c.12817C>T)?

AlphaMissense predicts likely benign (score 0.298) — an in-silico prediction, not a clinical call.

PLEC p.Pro4273Ser

Q: How is Plectin-related limb-girdle muscular dystrophy R17 inherited?

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

c.12817C>T · rs202040785 · VCV196825

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.298 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.477%, afr)

Conditions

autosomal recessive limb-girdle muscular dystrophy type 2Q

Computational evidence

Protein change
AlphaMissense	0.298	likely benign
REVEL	0.317	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.8, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 1,466 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	21.8	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL is an independent agreement signal.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P4410S vs ClinVar P4273S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.477% African / African-American · 358/75,032 alleles

Filtering AF 0.436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.42%

Overall 0.0258% 416/1,612,708 alleles · rare exomes 212/1,460,410 · genomes 204/152,298 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.477%	210
Admixed American	0.045%	2,223
Middle Eastern	0.033%	3,030
Remaining individualsnot grpmax-eligible	0.0288%	3,471
South Asian	0.0022%	45,541
European (non-Finnish)	0.000763%	131,095

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: PLEC
Protein: p.Pro4273Ser
Coding: c.12817C>T
MANE Select: NM_201384
dbSNP: rs202040785
Type: single nucleotide variant
Location: chr8:143917004 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)

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

Disease context

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

Also linked: epidermolysis bullosa simplex 5A, Ogna type epidermolysis bullosa simplex 5B, with muscular dystrophy epidermolysis bullosa simplex 5C, with pyloric atresia epidermolysis bullosa simplex with nail dystrophy

For Plectin-related limb-girdle muscular dystrophy R17 (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood

Similar variants

PLEC p.Pro4273Arg Uncertain significance ★ same residue
PLEC p.Arg1490Ter Pathogenic/Likely pathogenic ★★ same condition
PLEC p.Arg1973Trp Pathogenic ★★ ⚠ same condition
PLEC p.Arg2027Ter Pathogenic ★★ same condition
PLEC p.Arg2292Ter Pathogenic ★★ same condition
PLEC p.Arg2324Ter Pathogenic ★★ same condition
PLEC p.Arg2394Ter Pathogenic ★★ same condition
PLEC p.Arg559Ter 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/plec-p-pro4273ser (accessed [today's date]).

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