Is NR2F2 p.Ser68Arg (c.204C>G) pathogenic?

NR2F2 p.Ser68Arg (c.204C>G) is classified Uncertain significance in NR2F2 (ClinVar, Single submitter, 1 submitter; last evaluated 2019-10-16). AlphaMissense: ambiguous (0.4391); Very rare (popmax 0.000858%, nfe); Associated with congenital heart defects, multiple types, 4.

What condition is associated with NR2F2 p.Ser68Arg (c.204C>G)?

NR2F2 p.Ser68Arg (c.204C>G) is associated with congenital heart defects, multiple types, 4 (ClinVar).

How common is NR2F2 p.Ser68Arg (c.204C>G) in the general population?

NR2F2 p.Ser68Arg (c.204C>G) is very rare (popmax 0.000858%, nfe) (gnomAD).

What do computational predictors say about NR2F2 p.Ser68Arg (c.204C>G)?

AlphaMissense predicts ambiguous (score 0.4391) — an in-silico prediction, not a clinical call.

NR2F2 p.Ser68Arg

c.204C>G · rs1381103214 · VCV640947

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4391 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000858%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Conditions

congenital heart defects, multiple types, 4

Computational evidence

Protein change
AlphaMissense	0.4391	ambiguous
REVEL	0.261	benign-leaning
SaProt	LLR -8.90	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1	GERP 0.17, phastCons 1
Regional constraint	o/e 0.97	unconstrained · MANE · 206 bp · p 0.79 · regional, not allelic
Overall
CADD	19.83	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 0.000858% European (non-Finnish) · 10/1,166,020 alleles

Filtering AF 0.000434% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000316%

Overall 0.000631% 10/1,584,604 alleles · very rare exomes 10/1,432,460 · genomes 0/152,144 · joint denominator

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.Ser68Arg
Coding: c.204C>G
MANE Select: NM_021005
dbSNP: rs1381103214
Type: single nucleotide variant
Location: chr15:96332309 (GRCh38)
Gene constraint: LOEUF 0.197 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 77.94 · 1 PDB
Residue 68: 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.Ser68Asn Uncertain significance ★ ⚠ same residue
NR2F2 p.Ser68Gly Likely benign ★ same residue
NR2F2 p.Ser341Tyr Pathogenic/Likely pathogenic ★★ same condition
NR2F2 p.Trp249Ter Pathogenic/Likely pathogenic ★★ same condition
NR2F2 p.Ala2Ser Uncertain significance ★★ ⚠ same condition
NR2F2 p.Gly180Arg Uncertain significance ★★ ⚠ same condition
NR2F2 p.Gly361Arg Uncertain significance ★★ ⚠ same condition
NR2F2 p.His90Arg Uncertain significance ★★ ⚠ 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-ser68arg (accessed [today's date]).

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