Is PHF8 p.Tyr347= (c.1041T>C) pathogenic?

PHF8 p.Tyr347= (c.1041T>C) is classified Likely benign in PHF8 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2020-06-02). Very rare (popmax 0.000842%, nfe); Associated with PHF8-related disorder.

What condition is associated with PHF8 p.Tyr347= (c.1041T>C)?

PHF8 p.Tyr347= (c.1041T>C) is associated with PHF8-related disorder (ClinVar).

How common is PHF8 p.Tyr347= (c.1041T>C) in the general population?

PHF8 p.Tyr347= (c.1041T>C) is very rare (popmax 0.000842%, nfe) (gnomAD).

PHF8 p.Tyr347=

c.1041T>C · rs1422286175 · VCV3035919

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.000842%, nfe)

Conditions

PHF8-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.354	indeterminate
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.5	GERP 0.44, phastCons 1
Overall
CADD	8.579	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000842% European (non-Finnish) · 7/831,619 alleles

Filtering AF 0.00035% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000225%

Overall 0.000701% 8/1,141,342 alleles · very rare exomes 8/1,028,137 · genomes 0/113,205 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00221%	45,333
European (non-Finnish)grpmax	0.000842%	118,803

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Tyr347=
Coding: c.1041T>C
MANE Select: NM_015107
dbSNP: rs1422286175
Type: single nucleotide variant
Location: chrX:54002255 (GRCh38)
Structure: AlphaFold pLDDT 63.30 · 6 PDB
Residue 347: the jmjc domain; a β-strand

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

Disease context

PHF8-related disorder

Similar variants

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.Pro738= Likely benign same condition
PHF8 c.783+2del Likely pathogenic ★ same condition
PHF8 p.Lys833fs Likely pathogenic ★ same condition
PHF8 p.Arg240Ter Likely pathogenic ★★ same type

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-tyr347 (accessed [today's date]).

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