Is PHF12 p.Arg366Trp (c.1096C>T) pathogenic?

PHF12 p.Arg366Trp (c.1096C>T) is classified Uncertain significance in PHF12 (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-11). AlphaMissense: ambiguous (0.4572); Ultra-rare (popmax 0.0668%, eas); Associated with complex neurodevelopmental disorder.

What condition is associated with PHF12 p.Arg366Trp (c.1096C>T)?

PHF12 p.Arg366Trp (c.1096C>T) is associated with complex neurodevelopmental disorder (ClinVar).

How common is PHF12 p.Arg366Trp (c.1096C>T) in the general population?

PHF12 p.Arg366Trp (c.1096C>T) is ultra-rare (popmax 0.0668%, eas) (gnomAD).

How is Non-specific syndromic intellectual disability inherited?

Typically Autosomal dominant, Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about PHF12 p.Arg366Trp (c.1096C>T)?

AlphaMissense predicts ambiguous (score 0.4572) — an in-silico prediction, not a clinical call.

PHF12 p.Arg366Trp

c.1096C>T · VCV4883436

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4572 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0668%, eas)

Conditions

complex neurodevelopmental disorder

Computational evidence

Protein change
AlphaMissense	0.4572	ambiguous
REVEL	0.53	indeterminate
SaProt	LLR -7.40	tolerated
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 12	GERP 2.3, phastCons 1
Regional constraint	o/e 0.93	unconstrained · MANE · 4,842 bp · p 0.13 · regional, not allelic
Overall
CADD	34.0	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 0.0668% East Asian · 30/44,890 alleles

Filtering AF 0.0481% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0417%

Overall 0.00248% 40/1,613,944 alleles · ultra-rare exomes 37/1,461,848 · genomes 3/152,096 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0668%	1,496
South Asian	0.0011%	91,076
European (non-Finnish)	0.000763%	131,115

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.Arg366Trp
Coding: c.1096C>T
MANE Select: NM_001033561
Type: single nucleotide variant
Location: chr17:28917323 (GRCh38)
Gene constraint: LOEUF 0.115 · pLI 1.00 · ClinGen HI 3/3 (gnomAD)
Structure: AlphaFold pLDDT 55.98 · 6 PDB
Residue 366: the 'interaction with sin3a' region

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

Disease context

complex neurodevelopmental disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Non-specific syndromic intellectual disability (Orphanet):

Inheritance: Autosomal dominant, Autosomal recessive, X-linked recessive
Onset: Childhood, Infancy

Similar variants

PHF12 p.Arg366Gln Uncertain significance ★ ⚠ same residue
PHF12 p.Gly771Asp Uncertain significance ★ ⚠ same condition
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-arg366trp (accessed [today's date]).

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