Is PHF8 p.Ala714Ser (c.2140G>T) pathogenic?

PHF8 p.Ala714Ser (c.2140G>T) is classified Uncertain significance in PHF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-02-24). AlphaMissense: likely benign (0.2621); Absent from gnomAD v4.1; Associated with PHF8-related disorder.

What condition is associated with PHF8 p.Ala714Ser (c.2140G>T)?

PHF8 p.Ala714Ser (c.2140G>T) is associated with PHF8-related disorder (ClinVar).

How common is PHF8 p.Ala714Ser (c.2140G>T) in the general population?

PHF8 p.Ala714Ser (c.2140G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHF8 p.Ala714Ser (c.2140G>T)?

AlphaMissense predicts likely benign (score 0.2621) — an in-silico prediction, not a clinical call.

PHF8 p.Ala714Ser

c.2140G>T · rs2519516946 · VCV2630649

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2621 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PHF8-related disorder

Computational evidence

Protein change
AlphaMissense	0.2621	likely benign
REVEL	0.211	benign-leaning
SaProt	LLR -5.65	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 7.6	GERP 2.9, phastCons 1
Regional constraint	o/e 0.48	unconstrained · MANE · 2,658 bp · p 3.7e-07 · regional, not allelic
Overall
CADD	23.3	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 A750S vs ClinVar A714S) — 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.Ala714Ser
Coding: c.2140G>T
MANE Select: NM_015107
dbSNP: rs2519516946
Type: single nucleotide variant
Location: chrX:53985217 (GRCh38)
Structure: AlphaFold pLDDT 63.30 · 6 PDB

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

Disease context

PHF8-related disorder

Similar variants

PHF8 p.Arg589Ter Likely pathogenic ★ same condition
PHF8 p.Pro854Leu Uncertain significance ★ ⚠ same condition
PHF8 c.-52T>C Likely benign same condition
PHF8 p.Pro738= Likely benign same condition
PHF8 p.Tyr347= Likely benign same condition
PHF8 c.783+2del Likely pathogenic ★ same condition
PHF8 p.Lys833fs Likely pathogenic ★ same condition
PHF8 p.Arg240Ter Likely pathogenic ★★ 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-ala714ser (accessed [today's date]).

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