Is FPGS p.Arg50His (c.149G>A) pathogenic?

FPGS p.Arg50His (c.149G>A) is classified Uncertain significance in FPGS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-15). AlphaMissense: likely benign (0.0828); Very rare (popmax 0.004%, afr).

How common is FPGS p.Arg50His (c.149G>A) in the general population?

FPGS p.Arg50His (c.149G>A) is very rare (popmax 0.004%, afr) (gnomAD).

What do computational predictors say about FPGS p.Arg50His (c.149G>A)?

AlphaMissense predicts likely benign (score 0.0828) — an in-silico prediction, not a clinical call.

FPGS p.Arg50His

c.149G>A · rs200706232 · VCV2593860

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0828 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.004%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0828	likely benign
REVEL	0.197	benign-leaning
SaProt	LLR -7.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>T here scores Δ0.49 · evaluated, not missing
Constraint at this position
Conservation	phyloP 8.5	GERP 1.8, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 1,383 bp · p 0.11 · regional, not allelic
Overall
CADD	29.7	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.004% African / African-American · 3/74,940 alleles

Filtering AF 0.00122% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00104%

Overall 0.00186% 30/1,613,976 alleles · very rare exomes 27/1,461,744 · genomes 3/152,232 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.004%	24,980
Admixed American	0.00333%	29,994
European (non-Finnish)	0.00186%	53,635
Remaining individualsnot grpmax-eligible	0.0016%	62,482
Finnishnot grpmax-eligible	0.00156%	64,018
South Asian	0.0011%	91,082

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: FPGS
Protein: p.Arg50His
Coding: c.149G>A
MANE Select: NM_004957
dbSNP: rs200706232
Type: single nucleotide variant
Location: chr9:127804295 (GRCh38)
Gene constraint: LOEUF 1.174 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.05

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

Similar variants

FPGS p.Ile22Val Benign ★★ same type
FPGS p.Ala10Ser Uncertain significance ★ ⚠ same type
FPGS p.Ala15Gly Uncertain significance ★ ⚠ same type
FPGS p.Ala19Gly Uncertain significance ★ ⚠ same type
FPGS p.Ala307Ser Uncertain significance ★ ⚠ same type
FPGS p.Ala395Thr Uncertain significance ★ ⚠ same type
FPGS p.Ala423Gly Uncertain significance ★ ⚠ same type
FPGS p.Ala451Thr 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/fpgs-p-arg50his (accessed [today's date]).

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