Is PHF8 p.Pro738= (c.2214G>A) pathogenic?

PHF8 p.Pro738= (c.2214G>A) is classified Likely benign in PHF8 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2023-08-03). Very rare (popmax 0.00796%, nfe); Associated with PHF8-related disorder.

What condition is associated with PHF8 p.Pro738= (c.2214G>A)?

PHF8 p.Pro738= (c.2214G>A) is associated with PHF8-related disorder (ClinVar).

How common is PHF8 p.Pro738= (c.2214G>A) in the general population?

PHF8 p.Pro738= (c.2214G>A) is very rare (popmax 0.00796%, nfe) (gnomAD).

PHF8 p.Pro738=

c.2214G>A · rs140518672 · VCV3055221

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00796%, nfe)

Conditions

PHF8-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.057	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.4	GERP -5.4, phastCons 0.001
Overall
CADD	2.078	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00796% European (non-Finnish) · 71/892,224 alleles

Filtering AF 0.00643% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0059%

Overall 0.00597% 72/1,205,144 alleles · very rare exomes 69/1,093,150 · genomes 3/111,994 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00796%	12,567
African / African-American	0.00175%	57,114

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.Pro738=
Coding: c.2214G>A
MANE Select: NM_015107
dbSNP: rs140518672
Type: single nucleotide variant
Location: chrX:53985143 (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.Pro738Leu Uncertain significance ★ ⚠ same residue
PHF8 p.Arg589Ter Likely pathogenic ★ same condition
PHF8 p.Ala714Ser Uncertain significance ★ ⚠ same condition
PHF8 p.Pro854Leu Uncertain significance ★ ⚠ same condition
PHF8 c.-52T>C 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

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-pro738 (accessed [today's date]).

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