Is NCOR2 p.Pro975His (c.2924C>A) pathogenic?

NCOR2 p.Pro975His (c.2924C>A) is classified Uncertain significance in NCOR2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-06-07). AlphaMissense: likely pathogenic (0.6965); Ultra-rare (popmax 0.0192%, eas).

How common is NCOR2 p.Pro975His (c.2924C>A) in the general population?

NCOR2 p.Pro975His (c.2924C>A) is ultra-rare (popmax 0.0192%, eas) (gnomAD).

What do computational predictors say about NCOR2 p.Pro975His (c.2924C>A)?

AlphaMissense predicts likely pathogenic (score 0.6965) — an in-silico prediction, not a clinical call.

NCOR2 p.Pro975His

c.2924C>A · rs200740729 · VCV2513755

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6965 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0192%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6965	likely pathogenic
REVEL	0.459	indeterminate
SaProt	LLR -7.88	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 1.4, phastCons 1
Regional constraint	o/e 0.99	unconstrained · MANE · 34 kb · p 0.77 · regional, not allelic
Overall
CADD	28.0	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 0.0192% East Asian · 7/36,390 alleles

Filtering AF 0.00896% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00631%

Overall 0.00266% 37/1,388,734 alleles · ultra-rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0192%	5,199
European (non-Finnish)	0.00264%	37,898
Finnishnot grpmax-eligible	0.00181%	55,208
African / African-American	0.00149%	67,302

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.Pro975His
Coding: c.2924C>A
MANE Select: NM_006312
dbSNP: rs200740729
Type: single nucleotide variant
Location: chr12:124363683 (GRCh38)
Gene constraint: LOEUF 0.448 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 41.00 · 36 PDB
Residue 975: the 'disordered' region

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

Similar variants

NCOR2 p.Ala1526Thr Uncertain significance ★★ ⚠ same type
NCOR2 p.Arg2174Cys Uncertain significance ★★ ⚠ same type
NCOR2 p.Arg2467Gln Uncertain significance ★★ ⚠ same type
NCOR2 p.Gly1520Ser Uncertain significance ★★ ⚠ same type
NCOR2 c.3986-17C>T Benign ★★ same type
NCOR2 c.6265+16T>C Benign ★★ same type
NCOR2 c.-36G>C Benign ★★ same type
NCOR2 p.Ala1699Thr Benign ★★ 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/ncor2-p-pro975his (accessed [today's date]).

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