Is NR2F2 p.Ala2Ser (c.4G>T) pathogenic?

NR2F2 p.Ala2Ser (c.4G>T) is classified Uncertain significance in NR2F2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2021-02-08). AlphaMissense: likely benign (0.293); Very rare (popmax 0.00154%, afr); Associated with congenital heart defects, multiple types, 4.

What condition is associated with NR2F2 p.Ala2Ser (c.4G>T)?

NR2F2 p.Ala2Ser (c.4G>T) is associated with congenital heart defects, multiple types, 4 (ClinVar).

How common is NR2F2 p.Ala2Ser (c.4G>T) in the general population?

NR2F2 p.Ala2Ser (c.4G>T) is very rare (popmax 0.00154%, afr) (gnomAD).

What do computational predictors say about NR2F2 p.Ala2Ser (c.4G>T)?

AlphaMissense predicts likely benign (score 0.293) — an in-silico prediction, not a clinical call.

NR2F2 p.Ala2Ser

c.4G>T · rs1236325542 · VCV958490

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.293 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00154%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

congenital heart defects, multiple types, 4

Computational evidence

Protein change
AlphaMissense	0.293	likely benign
REVEL	0.541	indeterminate
SaProt	LLR -6.10	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 1.2, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 206 bp · p 0.79 · regional, not allelic
Overall
CADD	28.6	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 0.00154% African / African-American · 1/64,824 alleles

Filtering AF 0.000908% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000735%

Overall 0.00127% 17/1,335,192 alleles · very rare exomes 14/1,183,414 · genomes 3/151,778 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00154%	64,824
European (non-Finnish)	0.00153%	65,200

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: NR2F2
Protein: p.Ala2Ser
Coding: c.4G>T
MANE Select: NM_021005
dbSNP: rs1236325542
Type: single nucleotide variant
Location: chr15:96332109 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 77.94 · 1 PDB
Residue 2: the 'disordered' region

Full NR2F2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

congenital heart defects, multiple types, 4 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NR2F2 p.Ser341Tyr Pathogenic/Likely pathogenic ★★ same condition
NR2F2 p.Trp249Ter Pathogenic/Likely pathogenic ★★ same condition
NR2F2 p.Gly180Arg Uncertain significance ★★ ⚠ same condition
NR2F2 p.Gly361Arg Uncertain significance ★★ ⚠ same condition
NR2F2 p.His90Arg Uncertain significance ★★ ⚠ same condition
NR2F2 p.Pro32Arg Uncertain significance ★★ ⚠ same condition
NR2F2 p.Thr358Met Uncertain significance ★★ ⚠ same condition
NR2F2 p.Arg119= 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/nr2f2-p-ala2ser (accessed [today's date]).

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