Is PHF8 p.Phe279Ser (c.836T>C) pathogenic?

PHF8 p.Phe279Ser (c.836T>C) is classified Pathogenic in PHF8 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2007-08-01). AlphaMissense: likely pathogenic (0.9965); Absent from gnomAD v4.1; Associated with syndromic X-linked intellectual disability Siderius type.

What condition is associated with PHF8 p.Phe279Ser (c.836T>C)?

PHF8 p.Phe279Ser (c.836T>C) is associated with syndromic X-linked intellectual disability Siderius type (ClinVar).

How common is PHF8 p.Phe279Ser (c.836T>C) in the general population?

PHF8 p.Phe279Ser (c.836T>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHF8 p.Phe279Ser (c.836T>C)?

AlphaMissense predicts likely pathogenic (score 0.9965) — an in-silico prediction, not a clinical call.

PHF8 p.Phe279Ser

c.836T>C · rs121918524 · VCV10800

Pathogenic No assertion criteria

Classification

Pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9965 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

syndromic X-linked intellectual disability Siderius type

Computational evidence

Protein change
AlphaMissense	0.9965	likely pathogenic ✓ concordant with ClinVar · top 7% in PHF8
REVEL	0.791	moderately pathogenic-leaning
SaProt	LLR -14.04	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · A>C here scores Δ0.75 · evaluated, not missing
Constraint at this position
Conservation	phyloP 6.9	phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 18 kb · p 7.6e-27 · regional, not allelic
Overall
CADD	27.2	PHRED · no single calibrated threshold — expert panels disagree

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM F315S vs ClinVar F279S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PHF8
Protein: p.Phe279Ser
Coding: c.836T>C
MANE Select: NM_015107
dbSNP: rs121918524
Type: single nucleotide variant
Location: chrX:54011232 (GRCh38)
Structure: AlphaFold pLDDT 63.30 · 6 PDB
Residue 315 UniProt numbering: the jmjc domain; a UniProt-annotated variant site (in mrxssd; abolishes histone methyltransferase activity; reduces transcriptional activation activity); an α-helix

Full PHF8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

syndromic X-linked intellectual disability Siderius type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHF8 p.Arg240Ter Likely pathogenic ★★ same condition
PHF8 p.Arg506Ter Pathogenic/Likely pathogenic ★★ same condition
PHF8 p.Arg753Ter Pathogenic/Likely pathogenic ★★ same condition
PHF8 p.Arg66His Uncertain significance ★★ ⚠ same condition
PHF8 p.Arg753Gln Uncertain significance ★★ ⚠ same condition
PHF8 p.Arg773Pro Uncertain significance ★★ ⚠ same condition
PHF8 p.Leu949Phe Uncertain significance ★★ ⚠ same condition
PHF8 p.Tyr706Cys 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/phf8-p-phe279ser (accessed [today's date]).

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