Is NCOR2 p.Phe457= (c.1371C>T) pathogenic?

NCOR2 p.Phe457= (c.1371C>T) is classified Likely benign in NCOR2 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-04-15). Rare (popmax 0.4%, nfe); Associated with NCOR2-related disorder.

What condition is associated with NCOR2 p.Phe457= (c.1371C>T)?

NCOR2 p.Phe457= (c.1371C>T) is associated with NCOR2-related disorder (ClinVar).

How common is NCOR2 p.Phe457= (c.1371C>T) in the general population?

NCOR2 p.Phe457= (c.1371C>T) is rare (popmax 0.4%, nfe) (gnomAD).

NCOR2 p.Phe457=

c.1371C>T · rs61751355 · VCV3033831

Likely benign No assertion criteria

Classification

Likely benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

rare (popmax 0.4%, 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 4.2	GERP 0.45, phastCons 1
Overall
CADD	11.75	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.4% European (non-Finnish) · 4,715/1,180,004 alleles

Filtering AF 0.39% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.386%

Overall 0.344% 5,551/1,614,058 alleles · rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.709%	141
European (non-Finnish)grpmax	0.4%	250
Remaining individualsnot grpmax-eligible	0.358%	279
Ashkenazi Jewishnot grpmax-eligible	0.135%	740
Amishnot grpmax-eligible	0.11%	912
Middle Eastern	0.066%	1,516
African / African-American	0.0546%	1,831
Admixed American	0.0483%	2,070
South Asian	0.0472%	2,118
East Asian	0.00223%	44,878

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Phe457=
Coding: c.1371C>T
MANE Select: NM_006312
dbSNP: rs61751355
Type: single nucleotide variant
Location: chr12:124422513 (GRCh38)
Gene constraint: LOEUF 0.448 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 41.00 · 36 PDB
Residue 457: the sant 1 domain; the 'deacetylase activation domain (dad)' region

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

Disease context

NCOR2-related disorder

Similar variants

NCOR2 p.Phe457Tyr Uncertain significance ★ ⚠ same residue
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

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-phe457 (accessed [today's date]).

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