Is PGF p.Val40Ala (c.119T>C) pathogenic?

PGF p.Val40Ala (c.119T>C) is classified Uncertain significance in PGF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-17). AlphaMissense: ambiguous (0.4053); Ultra-rare (popmax 0.0327%, afr).

How common is PGF p.Val40Ala (c.119T>C) in the general population?

PGF p.Val40Ala (c.119T>C) is ultra-rare (popmax 0.0327%, afr) (gnomAD).

What do computational predictors say about PGF p.Val40Ala (c.119T>C)?

AlphaMissense predicts ambiguous (score 0.4053) — an in-silico prediction, not a clinical call.

PGF p.Val40Ala

c.119T>C · VCV3931214

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4053 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0327%, afr)

Computational evidence

Protein change
AlphaMissense	0.4053	ambiguous
REVEL	0.31	indeterminate
SaProt	LLR -8.93	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 13 kb · p 0.75 · regional, not allelic
Overall
CADD	27.6	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 0.0327% African / African-American · 24/73,358 alleles

Filtering AF 0.0226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0191%

Overall 0.00154% 24/1,557,158 alleles · ultra-rare exomes 14/1,405,018 · genomes 10/152,140 · 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: PGF
Protein: p.Val40Ala
Coding: c.119T>C
MANE Select: NM_002632
Type: single nucleotide variant
Location: chr14:74949553 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 71.00 · 2 PDB

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

Similar variants

PIGF p.Cys83Trp Uncertain significance ★★ same type
PIGF p.Val62Ala Benign ★★ same type
PGF p.Ala21Thr Uncertain significance ★ ⚠ same type
PGF p.Ala54Val Uncertain significance ★ ⚠ same type
PGF p.Arg110Leu Uncertain significance ★ ⚠ same type
PGF p.Arg114Trp Uncertain significance ★ ⚠ same type
PGF p.Arg127Cys Uncertain significance ★ ⚠ same type
PGF p.Arg127His 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/pgf-p-val40ala (accessed [today's date]).

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