Is PHF2 p.Lys895Arg (c.2684A>G) pathogenic?

PHF2 p.Lys895Arg (c.2684A>G) is classified Uncertain significance in PHF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-09). AlphaMissense: likely benign (0.1034); Ultra-rare (popmax 0.0214%, nfe).

How common is PHF2 p.Lys895Arg (c.2684A>G) in the general population?

PHF2 p.Lys895Arg (c.2684A>G) is ultra-rare (popmax 0.0214%, nfe) (gnomAD).

What do computational predictors say about PHF2 p.Lys895Arg (c.2684A>G)?

AlphaMissense predicts likely benign (score 0.1034) — an in-silico prediction, not a clinical call.

PHF2 p.Lys895Arg

c.2684A>G · VCV3417618

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1034 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0214%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1034	likely benign
REVEL	0.077	moderately benign-leaning
SaProt	LLR -5.98	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 9.2	GERP 1.8, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 18 kb · p 7.2e-10 · regional, not allelic
Overall
CADD	19.38	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0214% European (non-Finnish) · 252/1,179,988 alleles

Filtering AF 0.0192% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0183%

Overall 0.0157% 254/1,613,952 alleles · ultra-rare exomes 251/1,461,654 · genomes 3/152,298 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0214%	4,683
Admixed American	0.00167%	60,024
Remaining individualsnot grpmax-eligible	0.0016%	62,494

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.Lys895Arg
Coding: c.2684A>G
MANE Select: NM_005392
Type: single nucleotide variant
Location: chr9:93674984 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.14 · 9 PDB
Residue 895: the 'disordered' region

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

Similar variants

PHF2 c.299+7T>A Benign ★★ same type
PHF2 c.789+10G>A Benign/Likely benign ★★ same type
PHF2 p.Asp103= Benign ★★ same type
PHF2 p.Leu645= Benign/Likely benign ★★ same type
PHF2 p.Pro786= Benign ★★ same type
PHF2 p.Pro988= Benign ★★ same type
PHF2 p.Ser725= Benign ★★ same type
PHF2 p.Ser738= Benign ★★ 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/phf2-p-lys895arg (accessed [today's date]).

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