Is PHF8 p.Phe455Ser (c.1364T>C) pathogenic?

PHF8 p.Phe455Ser (c.1364T>C) is classified Uncertain significance in PHF8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-03-29). AlphaMissense: likely pathogenic (0.5855); Very rare (popmax 0.00296%, eas); Associated with Inborn genetic diseases.

What condition is associated with PHF8 p.Phe455Ser (c.1364T>C)?

PHF8 p.Phe455Ser (c.1364T>C) is associated with Inborn genetic diseases (ClinVar).

How common is PHF8 p.Phe455Ser (c.1364T>C) in the general population?

PHF8 p.Phe455Ser (c.1364T>C) is very rare (popmax 0.00296%, eas) (gnomAD).

What do computational predictors say about PHF8 p.Phe455Ser (c.1364T>C)?

AlphaMissense predicts likely pathogenic (score 0.5855) — an in-silico prediction, not a clinical call.

PHF8 p.Phe455Ser

c.1364T>C · rs782471251 · VCV840299

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.5855 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00296%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5855	likely pathogenic
REVEL	0.217	benign-leaning
SaProt	LLR -3.14	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8.1	GERP 2.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.36 · regional, not allelic
Overall
CADD	24.0	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 F491S vs ClinVar F455S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00296% East Asian · 1/33,808 alleles

Overall 0.000274% 3/1,095,341 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00296%	33,808
Remaining individualsnot grpmax-eligible	0.0021%	47,561
European (non-Finnish)	0.000112%	893,017

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: PHF8
Protein: p.Phe455Ser
Coding: c.1364T>C
MANE Select: NM_015107
dbSNP: rs782471251
Type: single nucleotide variant
Location: chrX:53993863 (GRCh38)
Structure: AlphaFold pLDDT 63.30 · 6 PDB
Residue 455: an α-helix

Full PHF8 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

Similar variants

PHF8 p.Arg506Ter Pathogenic/Likely pathogenic ★★ same condition
PHF8 p.Ala770Pro Uncertain significance ★★ ⚠ same condition
PHF8 p.Arg240Gln Uncertain significance ★★ ⚠ same condition
PHF8 p.Arg438His Uncertain significance ★★ same condition
PHF8 p.Arg588Gln Uncertain significance ★★ ⚠ same condition
PHF8 p.Arg773Pro Uncertain significance ★★ ⚠ same condition
PHF8 p.Arg968Cys Uncertain significance ★★ ⚠ same condition
PHF8 p.Arg982Trp 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-phe455ser (accessed [today's date]).

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