Is FPGS p.Ser499Phe (c.1496C>T) pathogenic?

FPGS p.Ser499Phe (c.1496C>T) is classified Likely benign in FPGS (ClinVar, Single submitter, 1 submitter; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1161); Low-frequency (popmax 1.04%, amr).

How common is FPGS p.Ser499Phe (c.1496C>T) in the general population?

FPGS p.Ser499Phe (c.1496C>T) is low-frequency (popmax 1.04%, amr) (gnomAD).

What do computational predictors say about FPGS p.Ser499Phe (c.1496C>T)?

AlphaMissense predicts likely benign (score 0.1161) — an in-silico prediction, not a clinical call.

FPGS p.Ser499Phe

c.1496C>T · VCV3905101

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1161 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.04%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1161	likely benign
REVEL	0.155	moderately benign-leaning
SaProt	LLR -9.40	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 4.7	GERP 1.4, phastCons 0.86
Regional constraint	o/e 0.97	unconstrained · MANE · 4,907 bp · p 0.5 · regional, not allelic
Overall
CADD	19.37	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 1.04% Admixed American · 623/60,002 alleles

Filtering AF 0.971% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.944%

Overall 0.0427% 688/1,613,076 alleles · low-frequency

Ancestry group	Frequency	1 in
Admixed Americangrpmax	1.04%	96
Remaining individualsnot grpmax-eligible	0.056%	1,785
African / African-American	0.032%	3,127
European (non-Finnish)	0.000509%	196,639

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.Ser499Phe
Coding: c.1496C>T
MANE Select: NM_004957
Type: single nucleotide variant
Location: chr9:127813336 (GRCh38)
Gene constraint: LOEUF 1.174 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.05
Residue 499: a UniProt-annotated variant site (expression reduced by 2.11-fold; vmax with methotrexate as substrate is significantly reduced resulting in significantly decreased intrinsic clearance of methotrexate; apparent vmax for glutamic acid is reduced 5-fold; reaction velocity at 100 nmol/l of pemetrexed is significantly reduced and folic acid dose-response curve is shifted to the right which corresponds to 4.28-fold increase in the ec(50) for folic acid; ic(50) of methotrexate is 1.64-fold higher and accumulation of a lower ratio of long-chain methotrexate polyglutamates to short-chain polyglutamates is detected; all results are for isoform 2 variant in comparison to the wild-type of it)

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-ser499phe (accessed [today's date]).

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