Is PLEC p.Arg951Pro (c.2852G>C) pathogenic?

PLEC p.Arg951Pro (c.2852G>C) is classified Uncertain significance in PLEC (ClinVar, Single submitter, 1 submitter; last evaluated 2016-12-30). AlphaMissense: likely pathogenic (0.8438); Very rare (popmax 0.00017%, nfe).

How common is PLEC p.Arg951Pro (c.2852G>C) in the general population?

PLEC p.Arg951Pro (c.2852G>C) is very rare (popmax 0.00017%, nfe) (gnomAD).

What do computational predictors say about PLEC p.Arg951Pro (c.2852G>C)?

AlphaMissense predicts likely pathogenic (score 0.8438) — an in-silico prediction, not a clinical call.

PLEC p.Arg951Pro

c.2852G>C · rs782775290 · VCV448058

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8438 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00017%, nfe)

Computational evidence

Protein change
AlphaMissense	0.8438	likely pathogenic
REVEL	0.558	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 5.7	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	23.1	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 R1088P vs ClinVar R951P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00017% European (non-Finnish) · 2/1,179,248 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000125% 2/1,599,876 alleles · very rare exomes 2/1,447,532 · genomes 0/152,344 · 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.Arg951Pro
Coding: c.2852G>C
MANE Select: NM_201384
dbSNP: rs782775290
Type: single nucleotide variant
Location: chr8:143929717 (GRCh38)
Gene constraint: LOEUF 0.726 · pLI <0.01 (gnomAD)

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

Similar variants

PLEC p.Arg951Gln Uncertain significance ★★ same residue
PLEC p.Arg951Trp Uncertain significance ★★ same residue
PLEC p.Arg1490Ter Pathogenic/Likely pathogenic ★★ same type
PLEC p.Arg1973Trp Pathogenic ★★ ⚠ same type
PLEC p.Arg2027Ter Pathogenic ★★ same type
PLEC p.Arg2292Ter Pathogenic ★★ same type
PLEC p.Arg2324Ter Pathogenic ★★ same type
PLEC p.Arg2394Ter Pathogenic ★★ same type

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-arg951pro (accessed [today's date]).

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