Is FGFR3 p.Pro283Ser (c.847C>T) pathogenic?

FGFR3 p.Pro283Ser (c.847C>T) is classified Uncertain significance in FGFR3 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-28). AlphaMissense: likely pathogenic (0.9961); Very rare (popmax 0.00223%, eas); Associated with lacrimoauriculodentodigital syndrome 2.

What condition is associated with FGFR3 p.Pro283Ser (c.847C>T)?

FGFR3 p.Pro283Ser (c.847C>T) is associated with lacrimoauriculodentodigital syndrome 2 (ClinVar).

How common is FGFR3 p.Pro283Ser (c.847C>T) in the general population?

FGFR3 p.Pro283Ser (c.847C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about FGFR3 p.Pro283Ser (c.847C>T)?

AlphaMissense predicts likely pathogenic (score 0.9961) — an in-silico prediction, not a clinical call.

FGFR3 p.Pro283Ser

c.847C>T · rs769692611 · VCV2573045

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9961 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

lacrimoauriculodentodigital syndrome 2

Computational evidence

Protein change
AlphaMissense	0.9961	likely pathogenic · top 8% in FGFR3
REVEL	0.849	moderately pathogenic-leaning
SaProt	LLR -8.31	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.4	GERP 1.8, phastCons 1
Regional constraint	o/e 0.64	unconstrained · MANE · 627 bp · p 7.9e-08 · regional, not allelic
Overall
CADD	25.9	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 0.00223% East Asian · 1/44,872 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.000434% 7/1,612,796 alleles · very rare exomes 7/1,460,464 · genomes 0/152,332 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,872
Finnishnot grpmax-eligible	0.00159%	62,846
European (non-Finnish)	0.000424%	235,975

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.Pro283Ser
Coding: c.847C>T
MANE Select: NM_000142
dbSNP: rs769692611
Type: single nucleotide variant
Location: chr4:1801942 (GRCh38)
Gene constraint: LOEUF 0.458 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 75.25 · 16 PDB
Residue 283: the ig-like c2-type 3 domain; a β-strand

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

Disease context

lacrimoauriculodentodigital syndrome 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

FGFR3 p.Pro283Thr Uncertain significance ★★ ⚠ same residue
FGFR3 p.Arg248Cys Pathogenic ★★ same condition
FGFR3 p.Gly370Cys Pathogenic ★★ ⚠ same condition
FGFR3 p.Lys650Glu Pathogenic ★★ same condition
FGFR3 p.Pro250Arg Pathogenic/Likely pathogenic ★★ same condition
FGFR3 p.Ala765Val Uncertain significance ★★ ⚠ same condition
FGFR3 p.Asp513Asn Uncertain significance ★★ ⚠ same condition
FGFR3 p.Glu702Val Uncertain significance ★★ ⚠ same condition

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-pro283ser (accessed [today's date]).

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