Is PHF6 p.Lys133= (c.399A>G) pathogenic?

PHF6 p.Lys133= (c.399A>G) is classified Benign/Likely benign in PHF6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-07-28). Rare (popmax 0.169%, sas); Associated with Borjeson-Forssman-Lehmann syndrome.

What condition is associated with PHF6 p.Lys133= (c.399A>G)?

PHF6 p.Lys133= (c.399A>G) is associated with Borjeson-Forssman-Lehmann syndrome (ClinVar).

How common is PHF6 p.Lys133= (c.399A>G) in the general population?

PHF6 p.Lys133= (c.399A>G) is rare (popmax 0.169%, sas) (gnomAD).

PHF6 p.Lys133=

c.399A>G · rs780193840 · VCV391122

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

gnomAD v4.1

Rare

rare (popmax 0.169%, sas)

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 6.1	GERP 0.86, phastCons 1
Overall
CADD	9.833	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.169% South Asian · 96/56,691 alleles

Filtering AF 0.142% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.132%

Overall 0.00935% 113/1,208,864 alleles · rare exomes 102/1,097,282 · genomes 11/111,582 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.169%	591
Remaining individualsnot grpmax-eligible	0.0168%	5,947
East Asian	0.00296%	33,746
European (non-Finnish)	0.000894%	111,838

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.Lys133=
Coding: c.399A>G
MANE Select: NM_001015877
dbSNP: rs780193840
Type: single nucleotide variant
Location: chrX:134393933 (GRCh38)
Structure: AlphaFold pLDDT 73.45 · 2 PDB

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-lys133 (accessed [today's date]).

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