Is PHF6 p.Ile92Val (c.274A>G) pathogenic?

PHF6 p.Ile92Val (c.274A>G) is classified Benign/Likely benign in PHF6 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-12-28). AlphaMissense: likely benign (0.0894); Ultra-rare (popmax 0.0152%, amr); Associated with Borjeson-Forssman-Lehmann syndrome.

What condition is associated with PHF6 p.Ile92Val (c.274A>G)?

PHF6 p.Ile92Val (c.274A>G) is associated with Borjeson-Forssman-Lehmann syndrome (ClinVar).

How common is PHF6 p.Ile92Val (c.274A>G) in the general population?

PHF6 p.Ile92Val (c.274A>G) is ultra-rare (popmax 0.0152%, amr) (gnomAD).

What do computational predictors say about PHF6 p.Ile92Val (c.274A>G)?

AlphaMissense predicts likely benign (score 0.0894) — an in-silico prediction, not a clinical call.

PHF6 p.Ile92Val

c.274A>G · rs773176481 · VCV2295489

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0894 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0152%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Borjeson-Forssman-Lehmann syndrome

Computational evidence

Protein change
AlphaMissense	0.0894	likely benign
REVEL	0.378	indeterminate
SaProt	LLR -6.71	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 36 kb · p 6.2e-06 · regional, not allelic
Overall
CADD	22.8	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 0.0152% Admixed American · 7/46,064 alleles

Filtering AF 0.00709% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00504%

Overall 0.000578% 7/1,210,810 alleles · ultra-rare exomes 7/1,096,869 · genomes 0/113,941 · 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.Ile92Val
Coding: c.274A>G
MANE Select: NM_001015877
dbSNP: rs773176481
Type: single nucleotide variant
Location: chrX:134393534 (GRCh38)
Structure: AlphaFold pLDDT 73.45 · 2 PDB
Residue 92: 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.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-ile92val (accessed [today's date]).

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