Is PMPCB p.Phe327Ser (c.980T>C) pathogenic?

PMPCB p.Phe327Ser (c.980T>C) is classified Uncertain significance in PMPCB (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-13). AlphaMissense: ambiguous (0.4264); Ultra-rare (popmax 0.0167%, mid); Associated with Inborn genetic diseases.

What condition is associated with PMPCB p.Phe327Ser (c.980T>C)?

PMPCB p.Phe327Ser (c.980T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PMPCB p.Phe327Ser (c.980T>C) in the general population?

PMPCB p.Phe327Ser (c.980T>C) is ultra-rare (popmax 0.0167%, mid) (gnomAD).

What do computational predictors say about PMPCB p.Phe327Ser (c.980T>C)?

AlphaMissense predicts ambiguous (score 0.4264) — an in-silico prediction, not a clinical call.

PMPCB p.Phe327Ser

c.980T>C · rs1203302546 · VCV2208471

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4264 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0167%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4264	ambiguous
REVEL	0.1	moderately benign-leaning
SaProt	LLR -6.76	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP -0.93, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 15 kb · p 0.61 · regional, not allelic
Overall
CADD	24.9	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0167% Middle Eastern · 1/5,986 alleles

Overall 0.00025% 4/1,602,134 alleles · ultra-rare exomes 4/1,449,878 · genomes 0/152,256 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0167%	5,986
Remaining individualsnot grpmax-eligible	0.00161%	61,990
African / African-American	0.00134%	74,420
South Asian	0.00112%	89,100

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.Phe327Ser
Coding: c.980T>C
MANE Select: NM_004279
dbSNP: rs1203302546
Type: single nucleotide variant
Location: chr7:103309082 (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-phe327ser (accessed [today's date]).

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