Is PLEC p.Ala2147Val (c.6440C>T) pathogenic?

PLEC p.Ala2147Val (c.6440C>T) is classified Uncertain significance in PLEC (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-28). AlphaMissense: likely benign (0.0943); Ultra-rare (popmax 0.0849%, eas); Associated with epidermolysis bullosa simplex 5B, with muscular dystrophy.

What condition is associated with PLEC p.Ala2147Val (c.6440C>T)?

PLEC p.Ala2147Val (c.6440C>T) is associated with epidermolysis bullosa simplex 5B, with muscular dystrophy, epidermolysis bullosa simplex 5A, Ogna type, epidermolysis bullosa simplex 5C, with pyloric atresia (ClinVar).

How common is PLEC p.Ala2147Val (c.6440C>T) in the general population?

PLEC p.Ala2147Val (c.6440C>T) is ultra-rare (popmax 0.0849%, eas) (gnomAD).

What do computational predictors say about PLEC p.Ala2147Val (c.6440C>T)?

AlphaMissense predicts likely benign (score 0.0943) — an in-silico prediction, not a clinical call.

PLEC p.Ala2147Val

Q: How is Epidermolysis bullosa simplex with muscular dystrophy inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

c.6440C>T · rs201351000 · VCV1007881

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0943 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0849%, eas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Conditions

epidermolysis bullosa simplex 5B, with muscular dystrophy

Computational evidence

Protein change
AlphaMissense	0.0943	likely benign
REVEL	0.107	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 0.41
Regional constraint	o/e 1.08	unconstrained · MANE · 18 kb · p 4.9e-10 · regional, not allelic
Overall
CADD	12.89	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 A2284V vs ClinVar A2147V) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0849% East Asian · 38/44,782 alleles

Filtering AF 0.0635% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0561%

Overall 0.00331% 53/1,599,738 alleles · ultra-rare exomes 46/1,447,784 · genomes 7/151,954 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0849%	1,178
Remaining individualsnot grpmax-eligible	0.00322%	31,079
Admixed American	0.00167%	59,798
South Asian	0.0011%	90,602
European (non-Finnish)	0.000936%	106,852

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.Ala2147Val
Coding: c.6440C>T
MANE Select: NM_201384
dbSNP: rs201351000
Type: single nucleotide variant
Location: chr8:143923489 (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 5B, with muscular dystrophy — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

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

For Epidermolysis bullosa simplex with muscular dystrophy (Orphanet):

Inheritance: Autosomal recessive
Onset: Infancy, Neonatal

Similar variants

PLEC p.Ala2147= Benign ★★ 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-ala2147val (accessed [today's date]).

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