Is GFAP p.Val87Phe (c.259G>T) pathogenic?

GFAP p.Val87Phe (c.259G>T) is classified Conflicting classifications of pathogenicity in GFAP (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2025-04-28). AlphaMissense: likely pathogenic (0.978); Very rare (popmax 0.000254%, nfe).

How common is GFAP p.Val87Phe (c.259G>T) in the general population?

GFAP p.Val87Phe (c.259G>T) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about GFAP p.Val87Phe (c.259G>T)?

AlphaMissense predicts likely pathogenic (score 0.978) — an in-silico prediction, not a clinical call.

GFAP p.Val87Phe

c.259G>T · rs267607518 · VCV1351005

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.978 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.978	likely pathogenic · top 5% in GFAP
REVEL	0.959	strongly pathogenic-leaning
SaProt	LLR -14.54	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.7	GERP 1.9, phastCons 1
Regional constraint	o/e 0.26	constrained · MANE · 95 bp · p 5.1e-07 · regional, not allelic
Overall
CADD	32.0	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 0.000254% European (non-Finnish) · 3/1,180,054 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,258 alleles · very rare exomes 4/1,461,880 · genomes 0/152,378 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,508
European (non-Finnish)grpmax	0.000254%	393,351

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: GFAP
Protein: p.Val87Phe
Coding: c.259G>T
MANE Select: NM_002055
dbSNP: rs267607518
Type: single nucleotide variant
Location: chr17:44915228 (GRCh38)
Gene constraint: LOEUF 0.991 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.70 · 1 PDB
Residue 87: the if rod domain; the 'coil 1a' region

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

Similar variants

GFAP p.Val87Ile Pathogenic ★★ same residue
GFAP p.Val87Leu Pathogenic ★★ 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-val87phe (accessed [today's date]).

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