Is PHF12 p.Lys124Arg (c.371A>G) pathogenic?

PHF12 p.Lys124Arg (c.371A>G) is classified Uncertain significance in PHF12 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-28). AlphaMissense: likely benign (0.0911); Ultra-rare (popmax 0.0547%, afr).

How common is PHF12 p.Lys124Arg (c.371A>G) in the general population?

PHF12 p.Lys124Arg (c.371A>G) is ultra-rare (popmax 0.0547%, afr) (gnomAD).

What do computational predictors say about PHF12 p.Lys124Arg (c.371A>G)?

AlphaMissense predicts likely benign (score 0.0911) — an in-silico prediction, not a clinical call.

PHF12 p.Lys124Arg

c.371A>G · rs371850848 · VCV2372950

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0911 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0547%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0911	likely benign
REVEL	0.229	benign-leaning
SaProt	LLR -6.19	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 7.9	GERP 2, phastCons 1
Regional constraint	o/e 0.75	unconstrained · MANE · 3,016 bp · p 0.0025 · regional, not allelic
Overall
CADD	18.96	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 0.0547% African / African-American · 41/74,932 alleles

Filtering AF 0.0414% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0368%

Overall 0.00285% 46/1,614,116 alleles · ultra-rare exomes 21/1,461,894 · genomes 25/152,222 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0547%	1,828
Remaining individualsnot grpmax-eligible	0.0048%	20,829
Admixed American	0.00333%	30,005

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: PHF12
Protein: p.Lys124Arg
Coding: c.371A>G
MANE Select: NM_001033561
dbSNP: rs371850848
Type: single nucleotide variant
Location: chr17:28924253 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.98 · 6 PDB
Residue 124: the 'interaction with sin3a' region; the 'pbr' region; the 'disordered' region

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-lys124arg (accessed [today's date]).

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