Is PHF2 p.Arg516Ser (c.1548G>T) pathogenic?

PHF2 p.Arg516Ser (c.1548G>T) is classified Uncertain significance in PHF2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: ambiguous (0.4156); Very rare (popmax 0.00603%, nfe).

How common is PHF2 p.Arg516Ser (c.1548G>T) in the general population?

PHF2 p.Arg516Ser (c.1548G>T) is very rare (popmax 0.00603%, nfe) (gnomAD).

What do computational predictors say about PHF2 p.Arg516Ser (c.1548G>T)?

AlphaMissense predicts ambiguous (score 0.4156) — an in-silico prediction, not a clinical call.

PHF2 p.Arg516Ser

c.1548G>T · VCV4135665

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4156 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00603%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4156	ambiguous
REVEL	0.04	moderately benign-leaning
SaProt	LLR -7.37	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP -0.48	GERP -2.3, phastCons 0.015
Regional constraint	o/e 0.79	unconstrained · MANE · 18 kb · p 7.2e-10 · regional, not allelic
Overall
CADD	13.77	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 0.00603% European (non-Finnish) · 63/1,045,224 alleles

Filtering AF 0.00481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00437%

Overall 0.00468% 65/1,388,980 alleles · very rare exomes 62/1,254,838 · genomes 3/134,142 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00603%	16,591
Remaining individualsnot grpmax-eligible	0.00195%	51,282
African / African-American	0.00156%	63,974

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.Arg516Ser
Coding: c.1548G>T
MANE Select: NM_005392
Type: single nucleotide variant
Location: chr9:93660410 (GRCh38)
Gene constraint: LOEUF 0.329 · pLI 1.00 · ClinGen HI 1/3 (gnomAD)
Structure: AlphaFold pLDDT 62.14 · 9 PDB
Residue 516: 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-arg516ser (accessed [today's date]).

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