Is PMPCA p.Ser458Phe (c.1373C>T) pathogenic?

PMPCA p.Ser458Phe (c.1373C>T) is classified Uncertain significance in PMPCA (ClinVar, Single submitter, 1 submitter; last evaluated 2024-04-19). AlphaMissense: likely benign (0.1401); Ultra-rare (popmax 0.0188%, nfe).

How common is PMPCA p.Ser458Phe (c.1373C>T) in the general population?

PMPCA p.Ser458Phe (c.1373C>T) is ultra-rare (popmax 0.0188%, nfe) (gnomAD).

What do computational predictors say about PMPCA p.Ser458Phe (c.1373C>T)?

AlphaMissense predicts likely benign (score 0.1401) — an in-silico prediction, not a clinical call.

PMPCA p.Ser458Phe

c.1373C>T · rs150094306 · VCV2722824

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1401 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0188%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1401	likely benign
REVEL	0.023	moderately benign-leaning
SaProt	LLR -10.12	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.2	GERP 1.5, phastCons 0.95
Regional constraint	o/e 1.03	unconstrained · MANE · 13 kb · p 0.42 · regional, not allelic
Overall
CADD	19.41	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 0.0188% European (non-Finnish) · 222/1,179,828 alleles

Filtering AF 0.0167% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.016%

Overall 0.0148% 239/1,612,864 alleles · ultra-rare exomes 222/1,460,654 · genomes 17/152,210 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0188%	5,315
African / African-American	0.012%	8,324
Remaining individualsnot grpmax-eligible	0.0112%	8,913
Admixed American	0.00167%	59,984

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: PMPCA
Protein: p.Ser458Phe
Coding: c.1373C>T
MANE Select: NM_015160
dbSNP: rs150094306
Type: single nucleotide variant
Location: chr9:136421941 (GRCh38)
Gene constraint: LOEUF 1.111 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 88.46

Full PMPCA gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

INPP5E p.Tyr458= Likely benign ★★ same residue
INPP5E c.937-2A>G Pathogenic/Likely pathogenic ★★ same type
INPP5E p.Arg378Cys Pathogenic/Likely pathogenic ★★ same type
INPP5E p.Arg435Gln Pathogenic/Likely pathogenic ★★ same type
INPP5E p.Arg435Trp Pathogenic/Likely pathogenic ★★ same type
INPP5E p.Arg557His Pathogenic/Likely pathogenic ★★ same type
INPP5E p.Arg563His Likely pathogenic ★★ ⚠ same type
INPP5E p.Arg585Cys Pathogenic/Likely pathogenic ★★ same type

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/pmpca-p-ser458phe (accessed [today's date]).

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