Is PGF p.Arg49His (c.146G>A) pathogenic?

PGF p.Arg49His (c.146G>A) is classified Uncertain significance in PGF (ClinVar, Single submitter, 1 submitter; last evaluated 2025-11-03). AlphaMissense: likely benign (0.1959); Very rare (popmax 0.00351%, amr).

How common is PGF p.Arg49His (c.146G>A) in the general population?

PGF p.Arg49His (c.146G>A) is very rare (popmax 0.00351%, amr) (gnomAD).

What do computational predictors say about PGF p.Arg49His (c.146G>A)?

AlphaMissense predicts likely benign (score 0.1959) — an in-silico prediction, not a clinical call.

PGF p.Arg49His

c.146G>A · VCV4567175

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1959 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00351%, amr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1959	likely benign
REVEL	0.368	indeterminate
SaProt	LLR -11.29	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.6, phastCons 1
Regional constraint	o/e 0.98	unconstrained · MANE · 13 kb · p 0.75 · regional, not allelic
Overall
CADD	24.3	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 0.00351% Admixed American · 2/56,906 alleles

Filtering AF 0.00182% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00158%

Overall 0.00201% 32/1,588,116 alleles · very rare exomes 30/1,435,952 · genomes 2/152,164 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00351%	28,453
European (non-Finnish)	0.00257%	38,943

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.Arg49His
Coding: c.146G>A
MANE Select: NM_002632
Type: single nucleotide variant
Location: chr14:74949526 (GRCh38)
Gene constraint: LOEUF 0.783 · pLI 0.15 (gnomAD)
Structure: AlphaFold pLDDT 71.00 · 2 PDB
Residue 49: an α-helix

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-arg49his (accessed [today's date]).

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