Is PLEC p.Ala2129Ser (c.6385G>T) pathogenic?

PLEC p.Ala2129Ser (c.6385G>T) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-06-07). AlphaMissense: likely benign (0.1061); Ultra-rare (popmax 0.0778%, afr); Associated with epidermolysis bullosa simplex with nail dystrophy.

What condition is associated with PLEC p.Ala2129Ser (c.6385G>T)?

PLEC p.Ala2129Ser (c.6385G>T) is associated with epidermolysis bullosa simplex with nail dystrophy, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5B, with muscular dystrophy (ClinVar).

How common is PLEC p.Ala2129Ser (c.6385G>T) in the general population?

PLEC p.Ala2129Ser (c.6385G>T) is ultra-rare (popmax 0.0778%, afr) (gnomAD).

What do computational predictors say about PLEC p.Ala2129Ser (c.6385G>T)?

AlphaMissense predicts likely benign (score 0.1061) — an in-silico prediction, not a clinical call.

PLEC p.Ala2129Ser

c.6385G>T · rs782449012 · VCV471630

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.1061 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0778%, afr)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

epidermolysis bullosa simplex with nail dystrophy

Computational evidence

Protein change
AlphaMissense	0.1061	likely benign
REVEL	0.218	benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.9	phastCons 1
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	18.26	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 A2266S vs ClinVar A2129S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0778% African / African-American · 58/74,564 alleles

Filtering AF 0.0617% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0559%

Overall 0.00413% 66/1,598,240 alleles · ultra-rare exomes 34/1,446,620 · genomes 32/151,620 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0778%	1,286
Remaining individualsnot grpmax-eligible	0.00804%	12,430
Admixed American	0.00335%	29,884
European (non-Finnish)	8.49e-05%	1,178,216

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.Ala2129Ser
Coding: c.6385G>T
MANE Select: NM_201384
dbSNP: rs782449012
Type: single nucleotide variant
Location: chr8:143923544 (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

epidermolysis bullosa simplex with nail dystrophy — 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 autosomal recessive limb-girdle muscular dystrophy type 2Q

Similar variants

PLEC p.Ala2129Thr Uncertain significance ★ ⚠ same residue
PLEC p.Ala2129_Gln2130insArgAla 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

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-ala2129ser (accessed [today's date]).

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