Is PHF6 p.Arg166Lys (c.497G>A) pathogenic?

PHF6 p.Arg166Lys (c.497G>A) is classified Uncertain significance in PHF6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-11-20). AlphaMissense: likely benign (0.0604); Very rare (popmax 0.00123%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PHF6 p.Arg166Lys (c.497G>A)?

PHF6 p.Arg166Lys (c.497G>A) is associated with Inborn genetic diseases, Borjeson-Forssman-Lehmann syndrome (ClinVar).

How common is PHF6 p.Arg166Lys (c.497G>A) in the general population?

PHF6 p.Arg166Lys (c.497G>A) is very rare (popmax 0.00123%, nfe) (gnomAD).

What do computational predictors say about PHF6 p.Arg166Lys (c.497G>A)?

AlphaMissense predicts likely benign (score 0.0604) — an in-silico prediction, not a clinical call.

PHF6 p.Arg166Lys

c.497G>A · rs368966223 · VCV2502247

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.0604 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00123%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0604	likely benign
REVEL	0.264	benign-leaning
SaProt	LLR -9.11	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 10	GERP 2, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 36 kb · p 6.2e-06 · regional, not allelic
Overall
CADD	20.2	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00123% European (non-Finnish) · 11/894,900 alleles

Filtering AF 0.00066% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000482%

Overall 0.00091% 11/1,209,043 alleles · very rare exomes 9/1,097,624 · genomes 2/111,419 · 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.Arg166Lys
Coding: c.497G>A
MANE Select: NM_001015877
dbSNP: rs368966223
Type: single nucleotide variant
Location: chrX:134413569 (GRCh38)
Structure: AlphaFold pLDDT 73.45 · 2 PDB
Residue 166: the 'disordered' region

Full PHF6 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Borjeson-Forssman-Lehmann syndrome

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.Arg24Thr 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-arg166lys (accessed [today's date]).

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