Is PHF6 p.Ser176= (c.528A>G) pathogenic?

PHF6 p.Ser176= (c.528A>G) is classified Likely benign in PHF6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2023-10-05). Ultra-rare (popmax 0.0109%, nfe); Associated with Borjeson-Forssman-Lehmann syndrome.

What condition is associated with PHF6 p.Ser176= (c.528A>G)?

PHF6 p.Ser176= (c.528A>G) is associated with Borjeson-Forssman-Lehmann syndrome (ClinVar).

How common is PHF6 p.Ser176= (c.528A>G) in the general population?

PHF6 p.Ser176= (c.528A>G) is ultra-rare (popmax 0.0109%, nfe) (gnomAD).

PHF6 p.Ser176=

c.528A>G · rs150815514 · VCV756547

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, 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 -6.6	GERP -4.1
Overall
CADD	0.23	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0109% European (non-Finnish) · 98/895,075 alleles

Filtering AF 0.00919% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00844%

Overall 0.00818% 99/1,209,682 alleles · ultra-rare exomes 95/1,097,784 · genomes 4/111,898 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0109%	9,133
Remaining individualsnot grpmax-eligible	0.0021%	47,580

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.Ser176=
Coding: c.528A>G
MANE Select: NM_001015877
dbSNP: rs150815514
Type: single nucleotide variant
Location: chrX:134413600 (GRCh38)
Structure: AlphaFold pLDDT 73.45 · 2 PDB
Residue 176: the 'disordered' 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-ser176 (accessed [today's date]).

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