Is PHF8 p.Arg773Pro (c.2318G>C) pathogenic?

PHF8 p.Arg773Pro (c.2318G>C) is classified Uncertain significance in PHF8 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-06-09). AlphaMissense: ambiguous (0.404); Ultra-rare (popmax 0.023%, mid); Associated with Inborn genetic diseases.

What condition is associated with PHF8 p.Arg773Pro (c.2318G>C)?

PHF8 p.Arg773Pro (c.2318G>C) is associated with Inborn genetic diseases, syndromic X-linked intellectual disability Siderius type (ClinVar).

How common is PHF8 p.Arg773Pro (c.2318G>C) in the general population?

PHF8 p.Arg773Pro (c.2318G>C) is ultra-rare (popmax 0.023%, mid) (gnomAD).

What do computational predictors say about PHF8 p.Arg773Pro (c.2318G>C)?

AlphaMissense predicts ambiguous (score 0.404) — an in-silico prediction, not a clinical call.

PHF8 p.Arg773Pro

c.2318G>C · rs371107125 · VCV1804980

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.404 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.023%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.404	ambiguous
REVEL	0.12	moderately benign-leaning
SaProt	LLR -6.99	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	Δ0.21	acceptor gain · deltas
Constraint at this position
Conservation	phyloP 4.8	GERP 0.81, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 156 bp · p 0.44 · regional, not allelic
Overall
CADD	23.8	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 R809P vs ClinVar R773P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.023% Middle Eastern · 1/4,353 alleles

Overall 0.000165% 2/1,211,031 alleles · ultra-rare exomes 2/1,097,490 · genomes 0/113,541 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.023%	4,353
Remaining individualsnot grpmax-eligible	0.0021%	47,637

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.Arg773Pro
Coding: c.2318G>C
MANE Select: NM_015107
dbSNP: rs371107125
Type: single nucleotide variant
Location: chrX:53985039 (GRCh38)
Structure: AlphaFold pLDDT 63.30 · 6 PDB
Residue 809 UniProt numbering: the 'disordered' region

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

Also linked: syndromic X-linked intellectual disability Siderius type

Similar variants

PHF8 p.Arg773Cys Uncertain significance ★ ⚠ same residue
PHF8 p.Arg773His Uncertain significance ★ ⚠ same residue
PHF8 p.Arg240Ter Likely pathogenic ★★ same condition
PHF8 p.Arg506Ter Pathogenic/Likely pathogenic ★★ same condition
PHF8 p.Arg753Ter 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

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-arg773pro (accessed [today's date]).

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