Is PHF8 p.Arg782Pro (c.2345G>C) pathogenic?

PHF8 p.Arg782Pro (c.2345G>C) is classified Uncertain significance in PHF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2020-03-29). AlphaMissense: likely pathogenic (0.844); Very rare (popmax 0.000447%, nfe); Associated with syndromic X-linked intellectual disability Siderius type.

What condition is associated with PHF8 p.Arg782Pro (c.2345G>C)?

PHF8 p.Arg782Pro (c.2345G>C) is associated with syndromic X-linked intellectual disability Siderius type (ClinVar).

How common is PHF8 p.Arg782Pro (c.2345G>C) in the general population?

PHF8 p.Arg782Pro (c.2345G>C) is very rare (popmax 0.000447%, nfe) (gnomAD).

What do computational predictors say about PHF8 p.Arg782Pro (c.2345G>C)?

AlphaMissense predicts likely pathogenic (score 0.844) — an in-silico prediction, not a clinical call.

PHF8 p.Arg782Pro

c.2345G>C · rs782358977 · VCV1030462

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.844 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000447%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

syndromic X-linked intellectual disability Siderius type

Computational evidence

Protein change
AlphaMissense	0.844	likely pathogenic
REVEL	0.131	moderately benign-leaning
SaProt	LLR -7.76	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.9, phastCons 1
Regional constraint	o/e 1.11	unconstrained · MANE · 156 bp · p 0.44 · regional, not allelic
Overall
CADD	25.4	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 R818P vs ClinVar R782P) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000447% European (non-Finnish) · 4/894,819 alleles

Filtering AF 0.000105% ClinGen BA1/BS1 input FAF95, joint · FAF99 7.1e-05%

Overall 0.00033% 4/1,211,036 alleles · very rare exomes 4/1,097,401 · genomes 0/113,635 · joint denominator

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.Arg782Pro
Coding: c.2345G>C
MANE Select: NM_015107
dbSNP: rs782358977
Type: single nucleotide variant
Location: chrX:53985012 (GRCh38)
Structure: AlphaFold pLDDT 63.30 · 6 PDB
Residue 818 UniProt numbering: the 'disordered' region

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

Disease context

syndromic X-linked intellectual disability Siderius type — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

PHF8 p.Arg782Gln 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.Arg66His Uncertain significance ★★ ⚠ same condition
PHF8 p.Arg753Gln Uncertain significance ★★ ⚠ same condition
PHF8 p.Arg773Pro Uncertain significance ★★ ⚠ same condition
PHF8 p.Leu949Phe 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-arg782pro (accessed [today's date]).

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