Is PHF8 p.Pro568Ala (c.1702C>G) pathogenic?

PHF8 p.Pro568Ala (c.1702C>G) is classified Uncertain significance in PHF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-07-18). AlphaMissense: likely benign (0.0954); Very rare (popmax 0.00431%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PHF8 p.Pro568Ala (c.1702C>G)?

PHF8 p.Pro568Ala (c.1702C>G) is associated with Inborn genetic diseases (ClinVar).

How common is PHF8 p.Pro568Ala (c.1702C>G) in the general population?

PHF8 p.Pro568Ala (c.1702C>G) is very rare (popmax 0.00431%, nfe) (gnomAD).

What do computational predictors say about PHF8 p.Pro568Ala (c.1702C>G)?

AlphaMissense predicts likely benign (score 0.0954) — an in-silico prediction, not a clinical call.

PHF8 p.Pro568Ala

c.1702C>G · VCV4135795

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0954 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00431%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.0954	likely benign
REVEL	0.132	moderately benign-leaning
SaProt	LLR -6.28	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 2.6, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 12 kb · p 0.36 · regional, not allelic
Overall
CADD	17.21	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 P604A vs ClinVar P568A) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00431% European (non-Finnish) · 38/882,478 alleles

Filtering AF 0.0032% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0028%

Overall 0.00327% 39/1,194,195 alleles · very rare exomes 37/1,083,695 · genomes 2/110,500 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00431%	23,223
Remaining individualsnot grpmax-eligible	0.00212%	47,120

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.Pro568Ala
Coding: c.1702C>G
MANE Select: NM_015107
Type: single nucleotide variant
Location: chrX:53992764 (GRCh38)
Structure: AlphaFold pLDDT 63.30 · 6 PDB

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.Pro568Ser Uncertain significance ★ ⚠ 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-pro568ala (accessed [today's date]).

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