Is PLEC p.Pro4331Ser (c.12991C>T) pathogenic?

PLEC p.Pro4331Ser (c.12991C>T) is classified Uncertain significance in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2024-03-30). AlphaMissense: likely benign (0.0627); Very rare (popmax 0.0011%, sas); Associated with Inborn genetic diseases.

What condition is associated with PLEC p.Pro4331Ser (c.12991C>T)?

PLEC p.Pro4331Ser (c.12991C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PLEC p.Pro4331Ser (c.12991C>T) in the general population?

PLEC p.Pro4331Ser (c.12991C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about PLEC p.Pro4331Ser (c.12991C>T)?

AlphaMissense predicts likely benign (score 0.0627) — an in-silico prediction, not a clinical call.

PLEC p.Pro4331Ser

c.12991C>T · VCV3307454

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0627 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0627	likely benign
REVEL	0.046	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.6	GERP -2.1, phastCons 1
Regional constraint	o/e 0.85	unconstrained · MANE · 1,466 bp · p 3.6e-05 · regional, not allelic
Overall
CADD	14.13	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P4468S vs ClinVar P4331S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,060 alleles

Overall 6.2e-05% 1/1,612,794 alleles · very rare exomes 1/1,460,774 · genomes 0/152,020 · joint denominator

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.Pro4331Ser
Coding: c.12991C>T
MANE Select: NM_201384
Type: single nucleotide variant
Location: chr8:143916830 (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

Similar variants

PLEC p.Pro4331Leu Uncertain significance ★★ same residue
PLEC p.Ala1041Thr Uncertain significance ★★ ⚠ same condition
PLEC p.Ala1221Ser Uncertain significance ★★ ⚠ same condition
PLEC p.Ala1368Val Uncertain significance ★★ ⚠ same condition
PLEC p.Ala1390Val Uncertain significance ★★ ⚠ same condition
PLEC p.Ala1411Thr Uncertain significance ★★ ⚠ same condition
PLEC p.Ala1492Val Uncertain significance ★★ ⚠ same condition
PLEC p.Ala1513Val 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/plec-p-pro4331ser (accessed [today's date]).

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