Is PHF6 p.Ser138= (c.414C>T) pathogenic?

PHF6 p.Ser138= (c.414C>T) is classified Conflicting classifications of pathogenicity in PHF6 (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-05-05). Ultra-rare (popmax 0.0623%, eas); Associated with Borjeson-Forssman-Lehmann syndrome.

What condition is associated with PHF6 p.Ser138= (c.414C>T)?

PHF6 p.Ser138= (c.414C>T) is associated with Borjeson-Forssman-Lehmann syndrome (ClinVar).

How common is PHF6 p.Ser138= (c.414C>T) in the general population?

PHF6 p.Ser138= (c.414C>T) is ultra-rare (popmax 0.0623%, eas) (gnomAD).

PHF6 p.Ser138=

c.414C>T · rs200423380 · VCV211900

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

gnomAD v4.1

Rare

ultra-rare (popmax 0.0623%, eas)

Conditions

Borjeson-Forssman-Lehmann syndrome

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 0.71	GERP -1.8, phastCons 1
Overall
CADD	7.301	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0623% East Asian · 21/33,715 alleles

Filtering AF 0.0416% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.035%

Overall 0.00522% 63/1,207,879 alleles · ultra-rare exomes 51/1,096,788 · genomes 12/111,091 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0623%	1,605
South Asian	0.03%	3,338
Middle Eastern	0.023%	4,346
African / African-American	0.0105%	9,499
Remaining individualsnot grpmax-eligible	0.00421%	23,770
Admixed American	0.00219%	45,575
Finnishnot grpmax-eligible	0.00216%	46,266
European (non-Finnish)	0.00157%	63,857

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.Ser138=
Coding: c.414C>T
MANE Select: NM_001015877
dbSNP: rs200423380
Type: single nucleotide variant
Location: chrX:134393948 (GRCh38)
Structure: AlphaFold pLDDT 73.45 · 2 PDB
Residue 138: a modified residue (phosphoserine)

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-ser138 (accessed [today's date]).

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