Is PHF2 p.Pro480Leu (c.1439C>T) pathogenic?

PHF2 p.Pro480Leu (c.1439C>T) is classified Likely benign in PHF2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2022-07-29). AlphaMissense: likely benign (0.074); Rare (popmax 0.417%, nfe); Associated with PHF2-related disorder.

What condition is associated with PHF2 p.Pro480Leu (c.1439C>T)?

PHF2 p.Pro480Leu (c.1439C>T) is associated with PHF2-related disorder (ClinVar).

How common is PHF2 p.Pro480Leu (c.1439C>T) in the general population?

PHF2 p.Pro480Leu (c.1439C>T) is rare (popmax 0.417%, nfe) (gnomAD).

What do computational predictors say about PHF2 p.Pro480Leu (c.1439C>T)?

AlphaMissense predicts likely benign (score 0.074) — an in-silico prediction, not a clinical call.

PHF2 p.Pro480Leu

c.1439C>T · rs146063352 · VCV3040351

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.074 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.417%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

PHF2-related disorder

Computational evidence

Protein change
AlphaMissense	0.074	likely benign
REVEL	0.047	moderately benign-leaning
SaProt	LLR -7.28	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 5.8	GERP 0.21, phastCons 1
Regional constraint	o/e 0.79	unconstrained · MANE · 18 kb · p 7.2e-10 · regional, not allelic
Overall
CADD	26.3	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 0.417% European (non-Finnish) · 4,912/1,178,748 alleles

Filtering AF 0.407% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.403%

Overall 0.333% 5,369/1,610,468 alleles · rare exomes 5,013/1,458,368 · genomes 356/152,100 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.417%	240
Remaining individualsnot grpmax-eligible	0.278%	360
African / African-American	0.203%	493
Admixed American	0.104%	962
Finnishnot grpmax-eligible	0.0918%	1,089
Middle Eastern	0.0165%	6,060
South Asian	0.00996%	10,041
East Asian	0.00447%	22,389

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.Pro480Leu
Coding: c.1439C>T
MANE Select: NM_005392
dbSNP: rs146063352
Type: single nucleotide variant
Location: chr9:93660301 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.14 · 9 PDB
Residue 480: the 'disordered' region

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-pro480leu (accessed [today's date]).

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