Is PHF2 p.Arg66Trp (c.196C>T) pathogenic?

PHF2 p.Arg66Trp (c.196C>T) is classified Uncertain significance in PHF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-01-11). AlphaMissense: likely benign (0.2584); Very rare (popmax 0.000935%, nfe).

How common is PHF2 p.Arg66Trp (c.196C>T) in the general population?

PHF2 p.Arg66Trp (c.196C>T) is very rare (popmax 0.000935%, nfe) (gnomAD).

What do computational predictors say about PHF2 p.Arg66Trp (c.196C>T)?

AlphaMissense predicts likely benign (score 0.2584) — an in-silico prediction, not a clinical call.

PHF2 p.Arg66Trp

c.196C>T · rs368630398 · VCV2475531

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.2584 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000935%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.2584	likely benign
REVEL	0.267	benign-leaning
SaProt	LLR -11.51	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 2.8	GERP 1.8, phastCons 1
Regional constraint	o/e 0.60	unconstrained · MANE · 83 kb · p 8.8e-22 · regional, not allelic
Overall
CADD	24.4	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 0.000935% European (non-Finnish) · 11/1,176,622 alleles

Filtering AF 0.000502% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000367%

Overall 0.000809% 13/1,606,252 alleles · very rare exomes 11/1,454,124 · genomes 2/152,128 · joint denominator

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.0068%	14,705
European (non-Finnish)grpmax	0.000935%	106,966

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.Arg66Trp
Coding: c.196C>T
MANE Select: NM_005392
dbSNP: rs368630398
Type: single nucleotide variant
Location: chr9:93636422 (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 p.Arg66Gln Uncertain significance ★ ⚠ same residue
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

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-arg66trp (accessed [today's date]).

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