Is PLEC p.Met403Val (c.1207A>G) pathogenic?

PLEC p.Met403Val (c.1207A>G) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-17). AlphaMissense: likely benign (0.1927); Very rare (popmax 0.0055%, sas); Associated with Inborn genetic diseases.

What condition is associated with PLEC p.Met403Val (c.1207A>G)?

PLEC p.Met403Val (c.1207A>G) is associated with Inborn genetic diseases (ClinVar).

How common is PLEC p.Met403Val (c.1207A>G) in the general population?

PLEC p.Met403Val (c.1207A>G) is very rare (popmax 0.0055%, sas) (gnomAD).

What do computational predictors say about PLEC p.Met403Val (c.1207A>G)?

AlphaMissense predicts likely benign (score 0.1927) — an in-silico prediction, not a clinical call.

PLEC p.Met403Val

c.1207A>G · VCV4138947

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1927 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0055%, sas)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1927	likely benign
REVEL	0.568	indeterminate
SaProt	—	not scored · why
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	23.0	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 M540V vs ClinVar M403V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0055% South Asian · 5/90,978 alleles

Filtering AF 0.00211% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00137%

Overall 0.00174% 28/1,611,386 alleles · very rare exomes 27/1,459,362 · genomes 1/152,024 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0055%	18,196
European (non-Finnish)	0.00178%	56,163
Remaining individualsnot grpmax-eligible	0.0016%	62,390
African / African-American	0.00134%	74,850

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.Met403Val
Coding: c.1207A>G
MANE Select: NM_201384
Type: single nucleotide variant
Location: chr8:143934054 (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.Met403Thr 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-met403val (accessed [today's date]).

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