Is PMPCA p.Ala121Ser (c.361G>T) pathogenic?

PMPCA p.Ala121Ser (c.361G>T) is classified Uncertain significance in PMPCA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-10). AlphaMissense: likely benign (0.0747); Very rare (popmax 0.00403%, afr); Associated with Inborn genetic diseases.

What condition is associated with PMPCA p.Ala121Ser (c.361G>T)?

PMPCA p.Ala121Ser (c.361G>T) is associated with Inborn genetic diseases (ClinVar).

How common is PMPCA p.Ala121Ser (c.361G>T) in the general population?

PMPCA p.Ala121Ser (c.361G>T) is very rare (popmax 0.00403%, afr) (gnomAD).

What do computational predictors say about PMPCA p.Ala121Ser (c.361G>T)?

AlphaMissense predicts likely benign (score 0.0747) — an in-silico prediction, not a clinical call.

PMPCA p.Ala121Ser

c.361G>T · rs752569851 · VCV3215845

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0747 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00403%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0747	likely benign
REVEL	0.13	moderately benign-leaning
SaProt	LLR -6.48	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	Δ0.28	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 5	GERP 0.48, phastCons 0.98
Regional constraint	o/e 1.03	unconstrained · MANE · 13 kb · p 0.42 · regional, not allelic
Overall
CADD	20.5	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 0.00403% African / African-American · 3/74,516 alleles

Filtering AF 0.00107% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000496%

Overall 0.000189% 3/1,591,342 alleles · very rare exomes 0/1,439,128 · genomes 3/152,214 · 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: PMPCA
Protein: p.Ala121Ser
Coding: c.361G>T
MANE Select: NM_015160
dbSNP: rs752569851
Type: single nucleotide variant
Location: chr9:136412816 (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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

INPP5E p.Pro121Ser Uncertain significance ★★ ⚠ same residue
INPP5E p.Pro121= Likely benign ★★ same residue
INPP5E p.Ala105Val Uncertain significance ★★ ⚠ same condition
INPP5E p.Ala123Val Uncertain significance ★★ ⚠ same condition
INPP5E p.Ala291Val Uncertain significance ★★ ⚠ same condition
INPP5E p.Ala36Val Uncertain significance ★★ ⚠ same condition
INPP5E p.Ala503Ser Uncertain significance ★★ ⚠ same condition
INPP5E p.Arg251Pro Uncertain significance ★★ ⚠ 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/pmpca-p-ala121ser (accessed [today's date]).

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