Is PHF6 p.Cys99Phe (c.296G>T) pathogenic?

PHF6 p.Cys99Phe (c.296G>T) is classified Pathogenic in PHF6 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2002-12-01). AlphaMissense: likely pathogenic (0.9993); Absent from gnomAD v4.1; Associated with Borjeson-Forssman-Lehmann syndrome.

What condition is associated with PHF6 p.Cys99Phe (c.296G>T)?

PHF6 p.Cys99Phe (c.296G>T) is associated with Borjeson-Forssman-Lehmann syndrome (ClinVar).

How common is PHF6 p.Cys99Phe (c.296G>T) in the general population?

PHF6 p.Cys99Phe (c.296G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHF6 p.Cys99Phe (c.296G>T)?

AlphaMissense predicts likely pathogenic (score 0.9993) — an in-silico prediction, not a clinical call.

PHF6 p.Cys99Phe

c.296G>T · rs132630298 · VCV11064

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9993 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Borjeson-Forssman-Lehmann syndrome

Computational evidence

Protein change
AlphaMissense	0.9993	likely pathogenic ✓ concordant with ClinVar · top 6% in PHF6
REVEL	0.98	strongly pathogenic-leaning
SaProt	LLR -14.45	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 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 36 kb · p 6.2e-06 · regional, not allelic
Overall
CADD	31.0	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

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: PHF6
Protein: p.Cys99Phe
Coding: c.296G>T
MANE Select: NM_001015877
dbSNP: rs132630298
Type: single nucleotide variant
Location: chrX:134393556 (GRCh38)
Structure: AlphaFold pLDDT 73.45 · 2 PDB
Residue 99: a UniProt-annotated variant site (in bfls; loss of interaction with ubtf); the 'extended phd1 domain (ephd1)' region

Full PHF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Borjeson-Forssman-Lehmann syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHF6 p.Arg116Ter Pathogenic ★★ same condition
PHF6 p.Arg225Ter Pathogenic ★★ same condition
PHF6 p.Arg274Ter Pathogenic ★★ same condition
PHF6 p.Arg342Ter Pathogenic ★★ same condition
PHF6 p.Cys45Tyr Pathogenic ★★ same condition
PHF6 p.Met1Thr Pathogenic ★★ same condition
PHF6 p.Arg163His Uncertain significance ★★ ⚠ same condition
PHF6 p.Arg166Lys 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/phf6-p-cys99phe (accessed [today's date]).

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