Is NCOA2 p.Leu346Pro (c.1037T>C) pathogenic?

NCOA2 p.Leu346Pro (c.1037T>C) is classified Uncertain significance in NCOA2 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-02). AlphaMissense: likely benign (0.3387); Very rare (popmax 0.00439%, sas).

How common is NCOA2 p.Leu346Pro (c.1037T>C) in the general population?

NCOA2 p.Leu346Pro (c.1037T>C) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about NCOA2 p.Leu346Pro (c.1037T>C)?

AlphaMissense predicts likely benign (score 0.3387) — an in-silico prediction, not a clinical call.

NCOA2 p.Leu346Pro

c.1037T>C · rs746206192 · VCV2493093

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.3387 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.3387	likely benign
REVEL	0.201	benign-leaning
SaProt	LLR -5.55	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 9.4	GERP 2.1, phastCons 1
Regional constraint	o/e 0.61	unconstrained · MANE · 60 kb · p 1.9e-17 · regional, not allelic
Overall
CADD	24.4	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 0.00439% South Asian · 4/91,052 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000891%

Overall 0.000274% 4/1,460,900 alleles · very rare

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: NCOA2
Protein: p.Leu346Pro
Coding: c.1037T>C
MANE Select: NM_006540
dbSNP: rs746206192
Type: single nucleotide variant
Location: chr8:70159592 (GRCh38)
Gene constraint: LOEUF 0.211 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 48.53 · 383 PDB

Full NCOA2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NCOA2 p.Glu6= Benign ★★ same type
NCOA2 p.Pro1222= Benign ★★ same type
NCOA2 p.Ser551= Benign/Likely benign ★★ same type
NCOA2 p.Val1132Ile Likely benign ★★ same type
NCOA2 p.Ala1130Val Uncertain significance ★ ⚠ same type
NCOA2 p.Ala1199Ser Uncertain significance ★ ⚠ same type
NCOA2 p.Ala1228Val Uncertain significance ★ ⚠ same type
NCOA2 p.Ala1296Thr 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/ncoa2-p-leu346pro (accessed [today's date]).

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