Is PHF6 p.Ala296= (c.888C>G) pathogenic?

PHF6 p.Ala296= (c.888C>G) is classified Benign in PHF6 (ClinVar, Single submitter, 2 submitters; last evaluated 2024-05-29). Very rare (popmax 0.00863%, nfe); Associated with Borjeson-Forssman-Lehmann syndrome.

What condition is associated with PHF6 p.Ala296= (c.888C>G)?

PHF6 p.Ala296= (c.888C>G) is associated with Borjeson-Forssman-Lehmann syndrome (ClinVar).

How common is PHF6 p.Ala296= (c.888C>G) in the general population?

PHF6 p.Ala296= (c.888C>G) is very rare (popmax 0.00863%, nfe) (gnomAD).

PHF6 p.Ala296=

c.888C>G · rs751710275 · VCV3047596

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00863%, nfe)

Conditions

Borjeson-Forssman-Lehmann syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.8	GERP 2.1, phastCons 1
Overall
CADD	12.46	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00863% European (non-Finnish) · 77/892,422 alleles

Filtering AF 0.007% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00647%

Overall 0.00671% 81/1,206,963 alleles · very rare exomes 78/1,094,744 · genomes 3/112,219 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00863%	11,590
Admixed American	0.00656%	15,253
Remaining individualsnot grpmax-eligible	0.00211%	47,492

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: PHF6
Protein: p.Ala296=
Coding: c.888C>G
MANE Select: NM_001015877
dbSNP: rs751710275
Type: single nucleotide variant
Location: chrX:134417222 (GRCh38)
Structure: AlphaFold pLDDT 73.45 · 2 PDB
Residue 296: the 'extended phd2 domain (ephd2)' 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-ala296 (accessed [today's date]).

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