Is PHF8 p.Ser285Phe (c.854C>T) pathogenic?

PHF8 p.Ser285Phe (c.854C>T) is classified Uncertain significance in PHF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-22). AlphaMissense: likely pathogenic (0.9121); Absent from gnomAD v4.1.

How common is PHF8 p.Ser285Phe (c.854C>T) in the general population?

PHF8 p.Ser285Phe (c.854C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHF8 p.Ser285Phe (c.854C>T)?

AlphaMissense predicts likely pathogenic (score 0.9121) — an in-silico prediction, not a clinical call.

PHF8 p.Ser285Phe

c.854C>T · VCV3369556

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9121 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9121	likely pathogenic
REVEL	0.779	moderately pathogenic-leaning
SaProt	LLR -14.93	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	phastCons 1
Regional constraint	o/e 0.30	constrained · MANE · 18 kb · p 7.6e-27 · regional, not allelic
Overall
CADD	29.8	PHRED · no single calibrated threshold — expert panels disagree

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

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

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM S321F vs ClinVar S285F) — 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.Ser285Phe
Coding: c.854C>T
MANE Select: NM_015107
Type: single nucleotide variant
Location: chrX:54011214 (GRCh38)
Structure: AlphaFold pLDDT 63.30 · 6 PDB
Residue 321 UniProt numbering: the jmjc domain

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

Similar variants

PHF8 p.Arg240Ter Likely pathogenic ★★ same type
PHF8 p.Arg506Ter Pathogenic/Likely pathogenic ★★ same type
PHF8 p.Arg753Ter Pathogenic/Likely pathogenic ★★ same type
PHF8 p.Gln539Ter Pathogenic ★★ same type
PHF8 p.Ser737Ter Pathogenic/Likely pathogenic ★★ same type
PHF8 p.Ala770Pro Uncertain significance ★★ ⚠ same type
PHF8 p.Ala888Ser Uncertain significance ★★ ⚠ same type
PHF8 p.Arg240Gln Uncertain significance ★★ ⚠ same type

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-ser285phe (accessed [today's date]).

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