Is FGF8 p.Pro243Ser (c.727C>T) pathogenic?

FGF8 p.Pro243Ser (c.727C>T) is classified Uncertain significance in FGF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-03). AlphaMissense: likely benign (0.0755); Ultra-rare (popmax 0.0443%, mid).

How common is FGF8 p.Pro243Ser (c.727C>T) in the general population?

FGF8 p.Pro243Ser (c.727C>T) is ultra-rare (popmax 0.0443%, mid) (gnomAD).

What do computational predictors say about FGF8 p.Pro243Ser (c.727C>T)?

AlphaMissense predicts likely benign (score 0.0755) — an in-silico prediction, not a clinical call.

FGF8 p.Pro243Ser

c.727C>T · VCV4909319

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0755 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0443%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.0755	likely benign
REVEL	0.352	indeterminate
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.9, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 111 bp · p 0.61 · regional, not allelic
Overall
CADD	25.4	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P232S vs ClinVar P243S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0443% Middle Eastern · 2/4,514 alleles

Filtering AF 0.00786% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0032%

Overall 0.000188% 3/1,594,298 alleles · ultra-rare exomes 2/1,442,134 · genomes 1/152,164 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0443%	2,257
European (non-Finnish)	8.53e-05%	1,171,902

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: FGF8
Protein: p.Pro243Ser
Coding: c.727C>T
MANE Select: NM_033163
Type: single nucleotide variant
Location: chr10:101770337 (GRCh38)
Gene constraint: LOEUF 0.765 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 81.34 · 1 PDB

Full FGF8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FGF8 c.157-1G>A Likely pathogenic ★★ same type
FGF8 p.Arg129Ter Pathogenic/Likely pathogenic ★★ same type
FGF8 p.Arg206Gln Likely pathogenic ★★ same type
FGF8 p.Thr119Met Likely pathogenic ★★ same type
FGF8 c.157-11A>G Uncertain significance ★★ same type
FGF8 p.Ala147Thr Uncertain significance ★★ ⚠ same type
FGF8 p.Ala31Glu Uncertain significance ★★ ⚠ same type
FGF8 p.Arg195Trp 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/fgf8-p-pro243ser (accessed [today's date]).

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