Is GFAP p.Arg66Pro (c.197G>C) pathogenic?

GFAP p.Arg66Pro (c.197G>C) is classified Likely pathogenic in GFAP (ClinVar, Single submitter, 1 submitter; last evaluated 2015-04-20). AlphaMissense: likely pathogenic (0.9239); Absent from gnomAD v4.1.

How common is GFAP p.Arg66Pro (c.197G>C) in the general population?

GFAP p.Arg66Pro (c.197G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about GFAP p.Arg66Pro (c.197G>C)?

AlphaMissense predicts likely pathogenic (score 0.9239) — an in-silico prediction, not a clinical call.

GFAP p.Arg66Pro

c.197G>C · rs797044569 · VCV372607

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9239 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9239	likely pathogenic ✓ concordant with ClinVar
REVEL	0.886	moderately pathogenic-leaning
SaProt	LLR -18.50	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.9, phastCons 1
Regional constraint	o/e 0.26	constrained · MANE · 95 bp · p 5.1e-07 · regional, not allelic
Overall
CADD	25.1	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: GFAP
Protein: p.Arg66Pro
Coding: c.197G>C
MANE Select: NM_002055
dbSNP: rs797044569
Type: single nucleotide variant
Location: chr17:44915290 (GRCh38)
Gene constraint: LOEUF 0.991 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.70 · 1 PDB
Residue 66: the 'head' region; a UniProt-annotated variant site (in alxdrd)

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

Similar variants

GFAP p.Arg66Gln Conflicting classifications of pathogenicity ★ ⚠ same residue
GFAP p.Arg66Trp Conflicting classifications of pathogenicity ★ ⚠ same residue
GFAP p.Arg239Cys Pathogenic ★★ same type
GFAP p.Arg239His Pathogenic ★★ same type
GFAP p.Arg239Leu Pathogenic ★★ same type
GFAP p.Arg258Cys Pathogenic ★★ ⚠ same type
GFAP p.Arg376Trp Pathogenic ★★ same type
GFAP p.Arg416Trp 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/gfap-p-arg66pro (accessed [today's date]).

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