Is PHF8 p.Pro826Ser (c.2476C>T) pathogenic?

PHF8 p.Pro826Ser (c.2476C>T) is classified Uncertain significance in PHF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-30). AlphaMissense: ambiguous (0.4976); Absent from gnomAD v4.1.

How common is PHF8 p.Pro826Ser (c.2476C>T) in the general population?

PHF8 p.Pro826Ser (c.2476C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHF8 p.Pro826Ser (c.2476C>T)?

AlphaMissense predicts ambiguous (score 0.4976) — an in-silico prediction, not a clinical call.

PHF8 p.Pro826Ser

c.2476C>T · rs1460758361 · VCV2582170

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4976 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Computational evidence

Protein change
AlphaMissense	0.4976	ambiguous
REVEL	0.304	indeterminate
SaProt	LLR -4.96	tolerated
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.7, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 44 kb · p 7.9e-07 · regional, not allelic
Overall
CADD	21.4	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 P862S vs ClinVar P826S) — 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.Pro826Ser
Coding: c.2476C>T
MANE Select: NM_015107
dbSNP: rs1460758361
Type: single nucleotide variant
Location: chrX:53962907 (GRCh38)
Structure: AlphaFold pLDDT 63.30 · 6 PDB
Residue 862 UniProt numbering: the 'disordered' region

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

Similar variants

PHF8 p.Pro826fs Likely pathogenic ★ same residue
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

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-pro826ser (accessed [today's date]).

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