Is PHF8 p.Arg983Ser (c.2947C>A) pathogenic?

PHF8 p.Arg983Ser (c.2947C>A) is classified Uncertain significance in PHF8 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-04). AlphaMissense: likely pathogenic (0.9786); Very rare (popmax 0.000792%, nfe); Associated with Inborn genetic diseases.

What condition is associated with PHF8 p.Arg983Ser (c.2947C>A)?

PHF8 p.Arg983Ser (c.2947C>A) is associated with Inborn genetic diseases (ClinVar).

How common is PHF8 p.Arg983Ser (c.2947C>A) in the general population?

PHF8 p.Arg983Ser (c.2947C>A) is very rare (popmax 0.000792%, nfe) (gnomAD).

What do computational predictors say about PHF8 p.Arg983Ser (c.2947C>A)?

AlphaMissense predicts likely pathogenic (score 0.9786) — an in-silico prediction, not a clinical call.

PHF8 p.Arg983Ser

c.2947C>A · rs1271484888 · VCV1797977

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9786 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000792%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.9786	likely pathogenic
REVEL	0.101	moderately benign-leaning
SaProt	LLR -5.10	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 9.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 1,274 bp · p 0.058 · regional, not allelic
Overall
CADD	23.1	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 R1019S vs ClinVar R983S) — verify the residue.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000792% European (non-Finnish) · 7/883,391 alleles

Filtering AF 0.000329% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000212%

Overall 0.00059% 7/1,187,288 alleles · very rare exomes 5/1,075,272 · genomes 2/112,016 · 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.Arg983Ser
Coding: c.2947C>A
MANE Select: NM_015107
dbSNP: rs1271484888
Type: single nucleotide variant
Location: chrX:53940219 (GRCh38)
Structure: AlphaFold pLDDT 63.30 · 6 PDB
Residue 1019 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

Similar variants

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
PHF8 p.Arg982Trp 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-arg983ser (accessed [today's date]).

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