Is PHF2 p.Ser275= (c.825G>A) pathogenic?

PHF2 p.Ser275= (c.825G>A) is classified Benign in PHF2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-01). Ultra-rare (popmax 0.0573%, afr); Associated with PHF2-related disorder.

What condition is associated with PHF2 p.Ser275= (c.825G>A)?

PHF2 p.Ser275= (c.825G>A) is associated with PHF2-related disorder (ClinVar).

How common is PHF2 p.Ser275= (c.825G>A) in the general population?

PHF2 p.Ser275= (c.825G>A) is ultra-rare (popmax 0.0573%, afr) (gnomAD).

PHF2 p.Ser275=

c.825G>A · rs139132481 · VCV3042745

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0573%, afr)

Conditions

PHF2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -7.4	GERP -3.2
Overall
CADD	3.999	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0573% African / African-American · 43/75,030 alleles

Filtering AF 0.0436% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0389%

Overall 0.0451% 728/1,613,808 alleles · ultra-rare exomes 641/1,461,520 · genomes 87/152,288 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.66%	60
Remaining individualsnot grpmax-eligible	0.141%	710
African / African-Americangrpmax	0.0573%	1,745
Middle Eastern	0.0165%	6,060
Admixed American	0.015%	6,669
East Asian	0.0111%	8,975
European (non-Finnish)	0.00763%	13,110

Ashkenazi Jewish 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: PHF2
Protein: p.Ser275=
Coding: c.825G>A
MANE Select: NM_005392
dbSNP: rs139132481
Type: single nucleotide variant
Location: chr9:93654448 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.14 · 9 PDB
Residue 275: the jmjc domain; an α-helix

Full PHF2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

PHF2-related disorder

Similar variants

PHF2 p.Gly527Ser Uncertain significance ★ ⚠ same condition
PHF2 p.Ser1020Thr Uncertain significance ★ ⚠ same condition
PHF2 p.Asp133= Likely benign same condition
PHF2 p.Gly629= Likely benign same condition
PHF2 p.His865= Likely benign same condition
PHF2 p.Leu548= Benign same condition
PHF2 p.Lys890= Likely benign same condition
PHF2 p.Pro273= Likely benign 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/phf2-p-ser275 (accessed [today's date]).

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