Is PLEC p.Pro4331Leu (c.12992C>T) pathogenic?

PLEC p.Pro4331Leu (c.12992C>T) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-12-21). AlphaMissense: likely benign (0.0751); Rare (popmax 0.247%, mid); Associated with Inborn genetic diseases.

What condition is associated with PLEC p.Pro4331Leu (c.12992C>T)?

PLEC p.Pro4331Leu (c.12992C>T) is associated with Inborn genetic diseases, multiple sclerosis, epidermolysis bullosa simplex 5A, Ogna type (ClinVar).

How common is PLEC p.Pro4331Leu (c.12992C>T) in the general population?

PLEC p.Pro4331Leu (c.12992C>T) is rare (popmax 0.247%, mid) (gnomAD).

What do computational predictors say about PLEC p.Pro4331Leu (c.12992C>T)?

AlphaMissense predicts likely benign (score 0.0751) — an in-silico prediction, not a clinical call.

PLEC p.Pro4331Leu

c.12992C>T · rs199651668 · VCV196854

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 12 submitters

AlphaMissense

likely benign

0.0751 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.247%, mid)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0751	likely benign
REVEL	0.39	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.9	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	23.8	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 P4468L vs ClinVar P4331L) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.247% Middle Eastern · 15/6,084 alleles

Filtering AF 0.152% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.123%

Overall 0.0158% 255/1,612,914 alleles · rare exomes 237/1,460,778 · genomes 18/152,136 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.247%	406
African / African-American	0.0401%	2,497
Remaining individualsnot grpmax-eligible	0.0256%	3,904
European (non-Finnish)	0.0155%	6,448
Admixed American	0.0133%	7,500
South Asian	0.00329%	30,361

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.Pro4331Leu
Coding: c.12992C>T
MANE Select: NM_201384
dbSNP: rs199651668
Type: single nucleotide variant
Location: chr8:143916829 (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

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: multiple sclerosis epidermolysis bullosa simplex 5A, Ogna type epidermolysis bullosa simplex 5B, with muscular dystrophy epidermolysis bullosa simplex 5C, with pyloric atresia autosomal recessive limb-girdle muscular dystrophy type 2Q epidermolysis bullosa simplex with nail dystrophy

Similar variants

PLEC p.Pro4331Ser 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-pro4331leu (accessed [today's date]).

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