Is PPME1 p.Val44Phe (c.130G>T) pathogenic?

PPME1 p.Val44Phe (c.130G>T) is classified Uncertain significance in PPME1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: ambiguous (0.3792); Very rare (popmax 0.00134%, afr).

How common is PPME1 p.Val44Phe (c.130G>T) in the general population?

PPME1 p.Val44Phe (c.130G>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about PPME1 p.Val44Phe (c.130G>T)?

AlphaMissense predicts ambiguous (score 0.3792) — an in-silico prediction, not a clinical call.

PPME1 p.Val44Phe

c.130G>T · VCV4142696

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3792 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3792	ambiguous
REVEL	0.121	moderately benign-leaning
SaProt	LLR -10.72	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 59 kb · p 0.3 · 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 · 1/74,862 alleles

Overall 0.000186% 3/1,611,884 alleles · very rare exomes 3/1,459,726 · genomes 0/152,158 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00134%	74,862
South Asian	0.0011%	90,780
European (non-Finnish)	8.48e-05%	1,178,912

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: PPME1
Protein: p.Val44Phe
Coding: c.130G>T
MANE Select: NM_016147
Type: single nucleotide variant
Location: chr11:74203756 (GRCh38)
Gene constraint: LOEUF 0.451 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 83.13 · 3 PDB
Residue 44: an α-helix

Full PPME1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PPME1 p.Ala98Glu Uncertain significance ★ ⚠ same type
PPME1 p.Arg12Leu Uncertain significance ★ ⚠ same type
PPME1 p.Arg16Leu Uncertain significance ★ ⚠ same type
PPME1 p.Arg199Trp Uncertain significance ★ ⚠ same type
PPME1 p.Arg228Cys Uncertain significance ★ ⚠ same type
PPME1 p.Arg32Gly Uncertain significance ★ ⚠ same type
PPME1 p.Arg39Gln Uncertain significance ★ ⚠ same type
PPME1 p.Arg68Gln 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/ppme1-p-val44phe (accessed [today's date]).

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