Is PMPCA p.Pro174Ala (c.520C>G) pathogenic?

PMPCA p.Pro174Ala (c.520C>G) is classified Uncertain significance in PMPCA (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-16). AlphaMissense: ambiguous (0.4243); Very rare (popmax 0.00134%, afr); Associated with Inborn genetic diseases.

What condition is associated with PMPCA p.Pro174Ala (c.520C>G)?

PMPCA p.Pro174Ala (c.520C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PMPCA p.Pro174Ala (c.520C>G) in the general population?

PMPCA p.Pro174Ala (c.520C>G) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about PMPCA p.Pro174Ala (c.520C>G)?

AlphaMissense predicts ambiguous (score 0.4243) — an in-silico prediction, not a clinical call.

PMPCA p.Pro174Ala

c.520C>G · rs368447845 · VCV2546745

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4243 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.4243	ambiguous
REVEL	0.614	indeterminate
SaProt	LLR -10.91	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 1.7, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 13 kb · p 0.42 · regional, not allelic
Overall
CADD	26.3	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 0.00134% African / African-American · 1/74,850 alleles

Filtering AF 0.000183% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000121%

Overall 0.000435% 7/1,610,134 alleles · very rare exomes 2/1,457,900 · genomes 5/152,234 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,850
European (non-Finnish)	0.00051%	196,084

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.Pro174Ala
Coding: c.520C>G
MANE Select: NM_015160
dbSNP: rs368447845
Type: single nucleotide variant
Location: chr9:136414635 (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.Arg174Ile Uncertain significance ★ ⚠ 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
INPP5E p.Arg297Gln 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-pro174ala (accessed [today's date]).

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