Is NFE2 p.Ser346Pro (c.1036T>C) pathogenic?

NFE2 p.Ser346Pro (c.1036T>C) is classified Uncertain significance in NFE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-10-18). AlphaMissense: ambiguous (0.5367); Ultra-rare (popmax 0.02%, amr).

How common is NFE2 p.Ser346Pro (c.1036T>C) in the general population?

NFE2 p.Ser346Pro (c.1036T>C) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about NFE2 p.Ser346Pro (c.1036T>C)?

AlphaMissense predicts ambiguous (score 0.5367) — an in-silico prediction, not a clinical call.

NFE2 p.Ser346Pro

c.1036T>C · rs748559800 · VCV3197051

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5367 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Computational evidence

Protein change
AlphaMissense	0.5367	ambiguous
REVEL	0.567	indeterminate
SaProt	LLR -11.12	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 11	GERP 2.3, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 2,871 bp · p 9.6e-06 · regional, not allelic
Overall
CADD	27.1	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 0.02% Admixed American · 12/60,010 alleles

Filtering AF 0.0115% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00898%

Overall 0.00124% 20/1,614,042 alleles · ultra-rare exomes 19/1,461,894 · genomes 1/152,148 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,001
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.0016%	62,486
African / African-American	0.00134%	74,904
European (non-Finnish)	0.000424%	236,007

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: NFE2
Protein: p.Ser346Pro
Coding: c.1036T>C
MANE Select: NM_001136023
dbSNP: rs748559800
Type: single nucleotide variant
Location: chr12:54292460 (GRCh38)
Gene constraint: LOEUF 0.798 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 67.50 · 1 PDB

Full NFE2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NFE2 p.Ala165Gly Uncertain significance ★ ⚠ same type
NFE2 p.Ala218Val Uncertain significance ★ ⚠ same type
NFE2 p.Arg168Gln Uncertain significance ★ ⚠ same type
NFE2 p.Arg169His Uncertain significance ★ ⚠ same type
NFE2 p.Arg296Gln Uncertain significance ★ ⚠ same type
NFE2 p.Asn282Thr Uncertain significance ★ ⚠ same type
NFE2 p.Asp248His Uncertain significance ★ ⚠ same type
NFE2 p.Asp332Val 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/nfe2-p-ser346pro (accessed [today's date]).

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