Is FGR p.Trp187Arg (c.559T>C) pathogenic?

FGR p.Trp187Arg (c.559T>C) is classified Uncertain significance in FGR (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-15). AlphaMissense: ambiguous (0.361); Very rare (popmax 8.47e-05%, nfe).

How common is FGR p.Trp187Arg (c.559T>C) in the general population?

FGR p.Trp187Arg (c.559T>C) is very rare (popmax 8.47e-05%, nfe) (gnomAD).

What do computational predictors say about FGR p.Trp187Arg (c.559T>C)?

AlphaMissense predicts ambiguous (score 0.361) — an in-silico prediction, not a clinical call.

FGR p.Trp187Arg

c.559T>C · VCV4024806

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.361 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.47e-05%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.361	ambiguous
REVEL	0.729	pathogenic-leaning
SaProt	LLR -8.24	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>T here scores Δ0.27 · evaluated, not missing
Constraint at this position
Conservation	phyloP 7.9	GERP 2.4, phastCons 1
Regional constraint	o/e 0.74	unconstrained · MANE · 11 kb · p 7.9e-12 · regional, not allelic
Overall
CADD	24.4	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 8.47e-05% European (non-Finnish) · 1/1,179,994 alleles

Overall 6.84e-05% 1/1,461,836 alleles · very rare

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: FGR
Protein: p.Trp187Arg
Coding: c.559T>C
MANE Select: NM_005248
Type: single nucleotide variant
Location: chr1:27616980 (GRCh38)
Gene constraint: LOEUF 0.556 · pLI 0.50 (gnomAD)
Structure: AlphaFold pLDDT 83.00 · 7 PDB
Residue 187: the sh2 domain; a β-strand

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

Similar variants

FGR c.533-8C>G Benign ★★ same type
FGR p.Asp254= Benign ★★ same type
FGR p.Ser122= Benign ★★ same type
FGR p.Ala30Thr Uncertain significance ★ ⚠ same type
FGR p.Ala395Thr Uncertain significance ★ ⚠ same type
FGR p.Ala60Thr Uncertain significance ★ ⚠ same type
FGR p.Ala60Val Uncertain significance ★ ⚠ same type
FGR p.Arg384Lys 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/fgr-p-trp187arg (accessed [today's date]).

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