Is PHF2 p.Arg157Trp (c.469C>T) pathogenic?

PHF2 p.Arg157Trp (c.469C>T) is classified Uncertain significance in PHF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-07). AlphaMissense: likely benign (0.3067); Ultra-rare (popmax 0.0168%, mid).

How common is PHF2 p.Arg157Trp (c.469C>T) in the general population?

PHF2 p.Arg157Trp (c.469C>T) is ultra-rare (popmax 0.0168%, mid) (gnomAD).

What do computational predictors say about PHF2 p.Arg157Trp (c.469C>T)?

AlphaMissense predicts likely benign (score 0.3067) — an in-silico prediction, not a clinical call.

PHF2 p.Arg157Trp

c.469C>T · VCV3888255

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3067 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0168%, mid)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3067	likely benign
REVEL	0.208	benign-leaning
SaProt	LLR -12.12	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3.1	GERP 0.7, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 83 kb · p 8.8e-22 · regional, not allelic
Overall
CADD	26.4	PHRED · no single calibrated threshold — expert panels disagree

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

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0168% Middle Eastern · 1/5,954 alleles

Filtering AF 0.000441% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000321%

Overall 0.000838% 13/1,551,162 alleles · ultra-rare exomes 13/1,399,284 · genomes 0/151,878 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0168%	5,954
Remaining individualsnot grpmax-eligible	0.00166%	60,100
South Asian	0.00119%	84,042
European (non-Finnish)	0.000872%	114,689

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.Arg157Trp
Coding: c.469C>T
MANE Select: NM_005392
Type: single nucleotide variant
Location: chr9:93649079 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.14 · 9 PDB

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-arg157trp (accessed [today's date]).

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