Is PHF8 p.Pro462Ser (c.1384C>T) pathogenic?

PHF8 p.Pro462Ser (c.1384C>T) is classified Uncertain significance in PHF8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-02-01). AlphaMissense: likely benign (0.1349); Very rare (popmax 0.0074%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PHF8 p.Pro462Ser (c.1384C>T)?

PHF8 p.Pro462Ser (c.1384C>T) is associated with Inborn genetic diseases (ClinVar).

How common is PHF8 p.Pro462Ser (c.1384C>T) in the general population?

PHF8 p.Pro462Ser (c.1384C>T) is very rare (popmax 0.0074%, nfe) (gnomAD).

What do computational predictors say about PHF8 p.Pro462Ser (c.1384C>T)?

AlphaMissense predicts likely benign (score 0.1349) — an in-silico prediction, not a clinical call.

PHF8 p.Pro462Ser

c.1384C>T · rs138652719 · VCV2020072

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1349 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0074%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1349	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -6.37	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 7.3	GERP 2.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.36 · regional, not allelic
Overall
CADD	19.95	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.

⚠ Isoform check: AlphaMissense numbered on a different transcript (AM P498S vs ClinVar P462S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0074% European (non-Finnish) · 66/891,867 alleles

Filtering AF 0.00597% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00544%

Overall 0.00547% 66/1,206,553 alleles · very rare

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.Pro462Ser
Coding: c.1384C>T
MANE Select: NM_015107
dbSNP: rs138652719
Type: single nucleotide variant
Location: chrX:53993843 (GRCh38)
Structure: AlphaFold pLDDT 63.30 · 6 PDB
Residue 462: 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.Pro462Ala Likely benign ★ same residue
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

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-pro462ser (accessed [today's date]).

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