Is NCOR2 p.Pro74= (c.222C>T) pathogenic?

NCOR2 p.Pro74= (c.222C>T) is classified Likely benign in NCOR2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-05-14). Ultra-rare (popmax 0.0738%, nfe); Associated with NCOR2-related disorder.

What condition is associated with NCOR2 p.Pro74= (c.222C>T)?

NCOR2 p.Pro74= (c.222C>T) is associated with NCOR2-related disorder (ClinVar).

How common is NCOR2 p.Pro74= (c.222C>T) in the general population?

NCOR2 p.Pro74= (c.222C>T) is ultra-rare (popmax 0.0738%, nfe) (gnomAD).

NCOR2 p.Pro74=

c.222C>T · rs375860971 · VCV3041399

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

ultra-rare (popmax 0.0738%, nfe)

Conditions

NCOR2-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -8.8	GERP -13
Overall
CADD	2.126	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0738% European (non-Finnish) · 870/1,179,582 alleles

Filtering AF 0.0697% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0681%

Overall 0.0589% 950/1,612,660 alleles · ultra-rare exomes 895/1,460,324 · genomes 55/152,336 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0738%	1,356
African / African-American	0.04%	2,501
Remaining individualsnot grpmax-eligible	0.0368%	2,715
Admixed American	0.03%	3,328
Middle Eastern	0.0165%	6,050
East Asian	0.00446%	22,415
South Asian	0.0044%	22,732
Finnishnot grpmax-eligible	0.00315%	31,721

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: NCOR2
Protein: p.Pro74=
Coding: c.222C>T
MANE Select: NM_006312
dbSNP: rs375860971
Type: single nucleotide variant
Location: chr12:124486452 (GRCh38)
Gene constraint: LOEUF 0.448 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 41.00 · 36 PDB

Full NCOR2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

NCOR2-related disorder

Similar variants

NCOR2 p.Ala1526Thr Uncertain significance ★★ ⚠ same condition
NCOR2 p.Arg2467Gln Uncertain significance ★★ ⚠ same condition
NCOR2 c.1329-4G>A Benign same condition
NCOR2 c.3242-9G>A Benign same condition
NCOR2 c.6411+8C>T Likely benign same condition
NCOR2 c.7364-5C>T Likely benign same condition
NCOR2 c.-6A>C Likely benign same condition
NCOR2 p.Ala1037= Benign same condition

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/ncor2-p-pro74 (accessed [today's date]).

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