Is FPGS p.Arg558His (c.1673G>A) pathogenic?

FPGS p.Arg558His (c.1673G>A) is classified Likely benign in FPGS (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-11). AlphaMissense: likely benign (0.0792); Very rare (popmax 0.00335%, amr).

How common is FPGS p.Arg558His (c.1673G>A) in the general population?

FPGS p.Arg558His (c.1673G>A) is very rare (popmax 0.00335%, amr) (gnomAD).

What do computational predictors say about FPGS p.Arg558His (c.1673G>A)?

AlphaMissense predicts likely benign (score 0.0792) — an in-silico prediction, not a clinical call.

FPGS p.Arg558His

c.1673G>A · VCV4026532

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0792 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00335%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0792	likely benign
REVEL	0.029	moderately benign-leaning
SaProt	LLR -7.49	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.98	GERP -3.2, phastCons 0.001
Regional constraint	o/e 0.97	unconstrained · MANE · 4,907 bp · p 0.5 · regional, not allelic
Overall
CADD	12.14	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 0.00335% Admixed American · 2/59,756 alleles

Filtering AF 0.000555% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000208%

Overall 0.000496% 8/1,611,640 alleles · very rare exomes 5/1,459,438 · genomes 3/152,202 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00335%	29,878
European (non-Finnish)	0.000509%	196,478

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.Arg558His
Coding: c.1673G>A
MANE Select: NM_004957
Type: single nucleotide variant
Location: chr9:127813513 (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-arg558his (accessed [today's date]).

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