Is PHF2 p.Ala76Val (c.227C>T) pathogenic?

PHF2 p.Ala76Val (c.227C>T) is classified Uncertain significance in PHF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.0679); Ultra-rare (popmax 0.0467%, afr).

How common is PHF2 p.Ala76Val (c.227C>T) in the general population?

PHF2 p.Ala76Val (c.227C>T) is ultra-rare (popmax 0.0467%, afr) (gnomAD).

What do computational predictors say about PHF2 p.Ala76Val (c.227C>T)?

AlphaMissense predicts likely benign (score 0.0679) — an in-silico prediction, not a clinical call.

PHF2 p.Ala76Val

c.227C>T · VCV4135661

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0679 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0467%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0679	likely benign
REVEL	0.039	moderately benign-leaning
SaProt	LLR -6.27	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 0.77	GERP -3.5, phastCons 0.25
Regional constraint	o/e 0.60	unconstrained · MANE · 83 kb · p 8.8e-22 · regional, not allelic
Overall
CADD	12.75	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 0.0467% African / African-American · 35/74,994 alleles

Filtering AF 0.0345% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0303%

Overall 0.0064% 103/1,610,404 alleles · ultra-rare exomes 74/1,458,124 · genomes 29/152,280 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0467%	2,143
Admixed American	0.0369%	2,708
Middle Eastern	0.0331%	3,024
East Asian	0.0112%	8,950
Remaining individualsnot grpmax-eligible	0.00481%	20,775
European (non-Finnish)	0.00288%	34,663
South Asian	0.00221%	45,156

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.Ala76Val
Coding: c.227C>T
MANE Select: NM_005392
Type: single nucleotide variant
Location: chr9:93636453 (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-ala76val (accessed [today's date]).

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