Is PHF6 p.Ser83Ala (c.247T>G) pathogenic?

PHF6 p.Ser83Ala (c.247T>G) is classified Uncertain significance in PHF6 (ClinVar, Multiple submitters, 3 submitters; last evaluated 2024-05-15). AlphaMissense: likely benign (0.2122); Ultra-rare (popmax 0.0109%, amr); Associated with Borjeson-Forssman-Lehmann syndrome.

What condition is associated with PHF6 p.Ser83Ala (c.247T>G)?

PHF6 p.Ser83Ala (c.247T>G) is associated with Borjeson-Forssman-Lehmann syndrome (ClinVar).

How common is PHF6 p.Ser83Ala (c.247T>G) in the general population?

PHF6 p.Ser83Ala (c.247T>G) is ultra-rare (popmax 0.0109%, amr) (gnomAD).

What do computational predictors say about PHF6 p.Ser83Ala (c.247T>G)?

AlphaMissense predicts likely benign (score 0.2122) — an in-silico prediction, not a clinical call.

PHF6 p.Ser83Ala

c.247T>G · rs762897039 · VCV1325935

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

likely benign

0.2122 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Borjeson-Forssman-Lehmann syndrome

Computational evidence

Protein change
AlphaMissense	0.2122	likely benign
REVEL	0.241	benign-leaning
SaProt	LLR -7.61	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 5.1	GERP 0.89, phastCons 1
Regional constraint	o/e 0.63	unconstrained · MANE · 36 kb · p 6.2e-06 · regional, not allelic
Overall
CADD	24.7	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 0.0109% Admixed American · 5/45,778 alleles

Filtering AF 0.00428% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00271%

Overall 0.000496% 6/1,210,162 alleles · ultra-rare exomes 5/1,097,510 · genomes 1/112,652 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0109%	9,156
European (non-Finnish)	0.000112%	895,047

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.Ser83Ala
Coding: c.247T>G
MANE Select: NM_001015877
dbSNP: rs762897039
Type: single nucleotide variant
Location: chrX:134393507 (GRCh38)
Structure: AlphaFold pLDDT 73.45 · 2 PDB
Residue 83: 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-ser83ala (accessed [today's date]).

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