Is FGFR3 p.Phe234Leu (c.700T>C) pathogenic?

FGFR3 p.Phe234Leu (c.700T>C) is classified Uncertain significance in FGFR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-12-10). AlphaMissense: likely pathogenic (0.7225); Very rare (popmax 0.00161%, nfe).

How common is FGFR3 p.Phe234Leu (c.700T>C) in the general population?

FGFR3 p.Phe234Leu (c.700T>C) is very rare (popmax 0.00161%, nfe) (gnomAD).

What do computational predictors say about FGFR3 p.Phe234Leu (c.700T>C)?

AlphaMissense predicts likely pathogenic (score 0.7225) — an in-silico prediction, not a clinical call.

FGFR3 p.Phe234Leu

c.700T>C · rs773302522 · VCV2819485

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7225 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.7225	likely pathogenic
REVEL	0.216	benign-leaning
SaProt	LLR -6.01	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · T>G here scores Δ0.79 · evaluated, not missing
Constraint at this position
Conservation	phyloP -0.019	GERP 0.018, phastCons 0.008
Regional constraint	o/e 0.64	unconstrained · MANE · 627 bp · p 7.9e-08 · regional, not allelic
Overall
CADD	19.38	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 0.00161% European (non-Finnish) · 19/1,179,036 alleles

Filtering AF 0.00103% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000831%

Overall 0.00124% 20/1,610,058 alleles · very rare exomes 18/1,458,160 · genomes 2/151,898 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00161%	62,054
Remaining individualsnot grpmax-eligible	0.0016%	62,372

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: FGFR3
Protein: p.Phe234Leu
Coding: c.700T>C
MANE Select: NM_000142
dbSNP: rs773302522
Type: single nucleotide variant
Location: chr4:1801704 (GRCh38)
Gene constraint: LOEUF 0.458 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 75.25 · 16 PDB
Residue 234: the ig-like c2-type 2 domain

Full FGFR3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

FGFR3 p.Ala391Glu Pathogenic ★★ same type
FGFR3 p.Arg248Cys Pathogenic ★★ same type
FGFR3 p.Arg621His Pathogenic/Likely pathogenic ★★ same type
FGFR3 p.Asn540Asp Pathogenic/Likely pathogenic ★★ same type
FGFR3 p.Asn540Lys Pathogenic ★★ same type
FGFR3 p.Asn540Ser Pathogenic/Likely pathogenic ★★ ⚠ same type
FGFR3 p.Asn540Thr Pathogenic/Likely pathogenic ★★ same type
FGFR3 p.Gly268Cys Pathogenic/Likely pathogenic ★★ 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/fgfr3-p-phe234leu (accessed [today's date]).

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