Is PHF12 p.Ser280Arg (c.838A>C) pathogenic?

PHF12 p.Ser280Arg (c.838A>C) is classified Uncertain significance in PHF12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-07). AlphaMissense: likely pathogenic (0.9987); Absent from gnomAD v4.1.

How common is PHF12 p.Ser280Arg (c.838A>C) in the general population?

PHF12 p.Ser280Arg (c.838A>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about PHF12 p.Ser280Arg (c.838A>C)?

AlphaMissense predicts likely pathogenic (score 0.9987) — an in-silico prediction, not a clinical call.

PHF12 p.Ser280Arg

c.838A>C · VCV3417597

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9987 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9987	likely pathogenic · top 5% in PHF12
REVEL	0.597	indeterminate
SaProt	LLR -12.52	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.8	GERP 2.3, phastCons 1
Regional constraint	o/e 0.43	unconstrained · MANE · 6,658 bp · p 1.8e-15 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: PHF12
Protein: p.Ser280Arg
Coding: c.838A>C
MANE Select: NM_001033561
Type: single nucleotide variant
Location: chr17:28919274 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.98 · 6 PDB

Full PHF12 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

PHF12 p.Leu324Met Uncertain significance ★★ ⚠ same type
PHF12 p.Ala152Ser Uncertain significance ★ ⚠ same type
PHF12 p.Ala171Val Uncertain significance ★ ⚠ same type
PHF12 p.Ala196Thr Uncertain significance ★ ⚠ same type
PHF12 p.Ala36Thr Uncertain significance ★ ⚠ same type
PHF12 p.Ala395Pro Uncertain significance ★ ⚠ same type
PHF12 p.Ala398Ser Uncertain significance ★ ⚠ same type
PHF12 p.Ala483Val Uncertain significance ★ ⚠ 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/phf12-p-ser280arg (accessed [today's date]).

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