Is GFRA2 p.Pro249Ser (c.745C>T) pathogenic?

GFRA2 p.Pro249Ser (c.745C>T) is classified Uncertain significance in GFRA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-07-26). AlphaMissense: likely benign (0.2443); Rare (popmax 0.147%, afr).

How common is GFRA2 p.Pro249Ser (c.745C>T) in the general population?

GFRA2 p.Pro249Ser (c.745C>T) is rare (popmax 0.147%, afr) (gnomAD).

What do computational predictors say about GFRA2 p.Pro249Ser (c.745C>T)?

AlphaMissense predicts likely benign (score 0.2443) — an in-silico prediction, not a clinical call.

GFRA2 p.Pro249Ser

c.745C>T · rs75502370 · VCV3099492

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2443 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.147%, afr)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2443	likely benign
REVEL	0.385	indeterminate
SaProt	LLR -13.39	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 1.6, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 95 kb · p 0.37 · regional, not allelic
Overall
CADD	27.5	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 0.147% African / African-American · 110/74,910 alleles

Filtering AF 0.125% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.116%

Overall 0.00787% 127/1,613,302 alleles · rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.147%	681
Remaining individualsnot grpmax-eligible	0.0176%	5,676
Admixed American	0.00834%	11,989
South Asian	0.0011%	91,064

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: GFRA2
Protein: p.Pro249Ser
Coding: c.745C>T
MANE Select: NM_001495
dbSNP: rs75502370
Type: single nucleotide variant
Location: chr8:21750637 (GRCh38)
Gene constraint: LOEUF 0.695 · pLI 0.10 (gnomAD)
Structure: AlphaFold pLDDT 75.99 · 5 PDB

Full GFRA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

GFRA2 p.Pro443Ser Benign ★★ same type
GFRA2 p.Ser449= Benign ★★ same type
GFRA2 p.Ala228Val Uncertain significance ★ same type
GFRA2 p.Ala230Thr Uncertain significance ★ ⚠ same type
GFRA2 p.Ala372Thr Uncertain significance ★ ⚠ same type
GFRA2 p.Ala375Gly Uncertain significance ★ ⚠ same type
GFRA2 p.Arg18Leu Uncertain significance ★ ⚠ same type
GFRA2 p.Arg18Pro 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/gfra2-p-pro249ser (accessed [today's date]).

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