Is PPIH p.Val12Met (c.34G>A) pathogenic?

PPIH p.Val12Met (c.34G>A) is classified Uncertain significance in PPIH (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: ambiguous (0.5348); Very rare (popmax 0.00133%, afr).

How common is PPIH p.Val12Met (c.34G>A) in the general population?

PPIH p.Val12Met (c.34G>A) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about PPIH p.Val12Met (c.34G>A)?

AlphaMissense predicts ambiguous (score 0.5348) — an in-silico prediction, not a clinical call.

PPIH p.Val12Met

c.34G>A · VCV3936674

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5348 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5348	ambiguous
REVEL	0.167	moderately benign-leaning
SaProt	LLR -11.45	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.5	GERP 2.5, phastCons 1
Regional constraint	o/e 1.21	unconstrained · MANE · 442 bp · p 0.14 · regional, not allelic
Overall
CADD	24.0	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 0.00133% African / African-American · 1/75,060 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000186% 3/1,614,186 alleles · very rare exomes 2/1,461,848 · genomes 1/152,338 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	75,060
European (non-Finnish)	0.000169%	589,998

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: PPIH
Protein: p.Val12Met
Coding: c.34G>A
MANE Select: NM_006347
Type: single nucleotide variant
Location: chr1:42658480 (GRCh38)
Gene constraint: LOEUF 0.784 · pLI 0.03 (gnomAD)
Structure: AlphaFold pLDDT 96.48 · 11 PDB
Residue 12: a β-strand

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

Similar variants

PPIH p.Ala2Glu Uncertain significance ★ ⚠ same type
PPIH p.Asn162Ser Uncertain significance ★ ⚠ same type
PPIH p.Phe14Leu Uncertain significance ★ ⚠ same type
PPIH p.Ser172Leu Uncertain significance ★ ⚠ same type
PPIH p.Thr127Ile Uncertain significance ★ ⚠ same type
PPIH p.Val24Ile Uncertain significance ★ ⚠ 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/ppih-p-val12met (accessed [today's date]).

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