Is PHF6 p.Ala41Val (c.122C>T) pathogenic?

PHF6 p.Ala41Val (c.122C>T) is classified Uncertain significance in PHF6 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-15). AlphaMissense: likely pathogenic (0.7783); Very rare (popmax 0.00218%, amr); Associated with Borjeson-Forssman-Lehmann syndrome.

What condition is associated with PHF6 p.Ala41Val (c.122C>T)?

PHF6 p.Ala41Val (c.122C>T) is associated with Borjeson-Forssman-Lehmann syndrome (ClinVar).

How common is PHF6 p.Ala41Val (c.122C>T) in the general population?

PHF6 p.Ala41Val (c.122C>T) is very rare (popmax 0.00218%, amr) (gnomAD).

What do computational predictors say about PHF6 p.Ala41Val (c.122C>T)?

AlphaMissense predicts likely pathogenic (score 0.7783) — an in-silico prediction, not a clinical call.

PHF6 p.Ala41Val

c.122C>T · rs760978695 · VCV1440192

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7783 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00218%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Borjeson-Forssman-Lehmann syndrome

Computational evidence

Protein change
AlphaMissense	0.7783	likely pathogenic
REVEL	0.712	pathogenic-leaning
SaProt	LLR -7.58	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 36 kb · p 6.2e-06 · regional, not allelic
Overall
CADD	24.6	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

Grpmax group 0.00218% Admixed American · 1/45,813 alleles

Overall 8.27e-05% 1/1,208,623 alleles · very rare exomes 1/1,096,572 · genomes 0/112,051 · joint denominator

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.Ala41Val
Coding: c.122C>T
MANE Select: NM_001015877
dbSNP: rs760978695
Type: single nucleotide variant
Location: chrX:134377739 (GRCh38)
Structure: AlphaFold pLDDT 73.45 · 2 PDB
Residue 41: 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.Ala41= Likely benign ★ same residue
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

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-ala41val (accessed [today's date]).

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