Is PHF6 p.His216= (c.648T>C) pathogenic?

PHF6 p.His216= (c.648T>C) is classified Benign/Likely benign in PHF6 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-07-06). Very rare (popmax 0.00659%, amr); Associated with Inborn genetic diseases.

What condition is associated with PHF6 p.His216= (c.648T>C)?

PHF6 p.His216= (c.648T>C) is associated with Inborn genetic diseases, Borjeson-Forssman-Lehmann syndrome (ClinVar).

How common is PHF6 p.His216= (c.648T>C) in the general population?

PHF6 p.His216= (c.648T>C) is very rare (popmax 0.00659%, amr) (gnomAD).

PHF6 p.His216=

c.648T>C · rs755211450 · VCV1753829

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

gnomAD v4.1

Rare

very rare (popmax 0.00659%, amr)

Conditions

Inborn genetic diseases

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 -1.4	GERP -4.1, phastCons 0.001
Overall
CADD	4.86	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00659% Admixed American · 3/45,557 alleles

Filtering AF 0.00175% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000884%

Overall 0.00298% 36/1,208,468 alleles · very rare exomes 32/1,097,146 · genomes 4/111,322 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.123%	816
Admixed Americangrpmax	0.00659%	15,186
Remaining individualsnot grpmax-eligible	0.00421%	23,780
European (non-Finnish)	0.000447%	223,548

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.His216=
Coding: c.648T>C
MANE Select: NM_001015877
dbSNP: rs755211450
Type: single nucleotide variant
Location: chrX:134413885 (GRCh38)
Structure: AlphaFold pLDDT 73.45 · 2 PDB
Residue 216: the 'extended phd2 domain (ephd2)' 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.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-his216 (accessed [today's date]).

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