Is PMPCB p.Ser462Ile (c.1385G>T) pathogenic?

PMPCB p.Ser462Ile (c.1385G>T) is classified Uncertain significance in PMPCB (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-21). AlphaMissense: likely benign (0.1196); Ultra-rare (popmax 0.0178%, eas); Associated with Inborn genetic diseases.

What condition is associated with PMPCB p.Ser462Ile (c.1385G>T)?

PMPCB p.Ser462Ile (c.1385G>T) is associated with Inborn genetic diseases (ClinVar).

How common is PMPCB p.Ser462Ile (c.1385G>T) in the general population?

PMPCB p.Ser462Ile (c.1385G>T) is ultra-rare (popmax 0.0178%, eas) (gnomAD).

What do computational predictors say about PMPCB p.Ser462Ile (c.1385G>T)?

AlphaMissense predicts likely benign (score 0.1196) — an in-silico prediction, not a clinical call.

PMPCB p.Ser462Ile

c.1385G>T · rs559942322 · VCV3215852

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1196 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0178%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1196	likely benign
REVEL	0.066	moderately benign-leaning
SaProt	LLR -7.35	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 15 kb · p 0.61 · regional, not allelic
Overall
CADD	22.7	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0178% East Asian · 8/44,862 alleles

Filtering AF 0.00884% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00641%

Overall 0.000496% 8/1,614,026 alleles · ultra-rare exomes 5/1,461,728 · genomes 3/152,298 · 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: PMPCB
Protein: p.Ser462Ile
Coding: c.1385G>T
MANE Select: NM_004279
dbSNP: rs559942322
Type: single nucleotide variant
Location: chr7:103312111 (GRCh38)
Gene constraint: LOEUF 1.085 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 87.48

Full PMPCB 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

PMPCB p.Arg209Gln Uncertain significance ★★ ⚠ same condition
PMPCB p.Arg325Cys Uncertain significance ★★ ⚠ same condition
PMPCB p.Asn97Ser Uncertain significance ★★ ⚠ same condition
PMPCB p.Gln46Lys Uncertain significance ★★ ⚠ same condition
PMPCB p.Ile160Thr Uncertain significance ★★ ⚠ same condition
PMPCB p.Leu119Met Uncertain significance ★★ ⚠ same condition
PMPCB p.Thr416Ala Uncertain significance ★★ ⚠ same condition
PMPCB p.Thr280Ser Likely benign ★★ 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/pmpcb-p-ser462ile (accessed [today's date]).

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