Is PHF12 p.Pro653Arg (c.1958C>G) pathogenic?

PHF12 p.Pro653Arg (c.1958C>G) is classified Uncertain significance in PHF12 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-31). AlphaMissense: likely benign (0.1236); Very rare (popmax 0.00167%, amr).

How common is PHF12 p.Pro653Arg (c.1958C>G) in the general population?

PHF12 p.Pro653Arg (c.1958C>G) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about PHF12 p.Pro653Arg (c.1958C>G)?

AlphaMissense predicts likely benign (score 0.1236) — an in-silico prediction, not a clinical call.

PHF12 p.Pro653Arg

c.1958C>G · rs768906971 · VCV3212075

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1236 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1236	likely benign
REVEL	0.34	indeterminate
SaProt	LLR -7.00	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.6	GERP 1.8, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,842 bp · p 0.13 · regional, not allelic
Overall
CADD	21.7	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 0.00167% Admixed American · 1/60,024 alleles

Overall 6.2e-05% 1/1,614,190 alleles · very rare exomes 1/1,461,894 · genomes 0/152,296 · joint denominator

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.Pro653Arg
Coding: c.1958C>G
MANE Select: NM_001033561
dbSNP: rs768906971
Type: single nucleotide variant
Location: chr17:28912613 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.98 · 6 PDB
Residue 653: the 'interaction with sin3a' region; the 'disordered' region

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

Similar variants

PHF12 p.Pro653Leu Uncertain significance ★ ⚠ same residue
PHF12 p.Pro653= Benign ★ same residue
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

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-pro653arg (accessed [today's date]).

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