Is FPGS p.Ile22Val (c.64A>G) pathogenic?

FPGS p.Ile22Val (c.64A>G) is classified Benign in FPGS (ClinVar, Multiple submitters, 2 submitters; last evaluated 2020-10-29). AlphaMissense: likely benign (0.0638); Common (popmax 97%, eas) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about FPGS p.Ile22Val (c.64A>G)?

AlphaMissense predicts likely benign (score 0.0638) — an in-silico prediction, not a clinical call.

FPGS p.Ile22Val

Q: How common is FPGS p.Ile22Val (c.64A>G) in the general population?

FPGS p.Ile22Val (c.64A>G) is common (popmax 97%, eas) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.64A>G · rs10760502 · VCV1232138

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0638 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 97%, eas) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0638	likely benign
REVEL	0.01	strongly benign-leaning
SaProt	LLR -4.67	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 2.1	GERP -2.1, phastCons 0.028
Regional constraint	o/e 1.16	unconstrained · MANE · 1,383 bp · p 0.11 · regional, not allelic
Overall
CADD	5.353	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 97% East Asian · 32,690/33,712 alleles

Filtering AF 96.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 95.7%

Overall 66.9% 976,949/1,461,332 alleles · common exomes 866,421/1,309,512 · genomes 110,528/151,820 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	97%	1
African / African-American	85.9%	1
Finnishnot grpmax-eligible	77.5%	1
South Asian	67.3%	1
Remaining individualsnot grpmax-eligible	66.3%	2
European (non-Finnish)	64.8%	2
Amishnot grpmax-eligible	63.7%	2
Admixed American	61.1%	2
Ashkenazi Jewishnot grpmax-eligible	57.7%	2
Middle Eastern	55%	2

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.Ile22Val
Coding: c.64A>G
MANE Select: NM_004957
dbSNP: rs10760502
Type: single nucleotide variant
Location: chr9:127802988 (GRCh38)
Gene constraint: LOEUF 1.174 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 83.05
Residue 22: a UniProt-annotated variant site (in)

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

Similar variants

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
FPGS p.Ala4Val 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-ile22val (accessed [today's date]).

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