Is NFE2L2 p.Pro233Ser (c.697C>T) pathogenic?

NFE2L2 p.Pro233Ser (c.697C>T) is classified Likely benign in NFE2L2 (ClinVar, Single submitter, 2 submitters; last evaluated 2025-12-19). AlphaMissense: likely benign (0.079); Rare (popmax 0.356%, eas).

How common is NFE2L2 p.Pro233Ser (c.697C>T) in the general population?

NFE2L2 p.Pro233Ser (c.697C>T) is rare (popmax 0.356%, eas) (gnomAD).

What do computational predictors say about NFE2L2 p.Pro233Ser (c.697C>T)?

AlphaMissense predicts likely benign (score 0.079) — an in-silico prediction, not a clinical call.

NFE2L2 p.Pro233Ser

c.697C>T · rs139187151 · VCV1664489

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.079 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.356%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.079	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -5.92	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 3.9	GERP 0.23, phastCons 1
Regional constraint	o/e 0.96	unconstrained · MANE · 2,016 bp · p 0.4 · regional, not allelic
Overall
CADD	1.409	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 0.356% East Asian · 160/44,890 alleles

Filtering AF 0.311% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.294%

Overall 0.0116% 187/1,614,164 alleles · rare exomes 164/1,461,846 · genomes 23/152,318 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.356%	281
Remaining individualsnot grpmax-eligible	0.0272%	3,677
Admixed American	0.005%	20,006
African / African-American	0.00133%	75,038
South Asian	0.0011%	91,088
European (non-Finnish)	0.000424%	236,001

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: NFE2L2
Protein: p.Pro233Ser
Coding: c.697C>T
MANE Select: NM_006164
dbSNP: rs139187151
Type: single nucleotide variant
Location: chr2:177231906 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.50 (gnomAD)
Structure: AlphaFold pLDDT 61.72 · 23 PDB

Full NFE2L2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NFE2L2 p.Pro233Thr Benign ★ same residue
NFE2L2 p.Ala249Ser Uncertain significance ★★ ⚠ same type
NFE2L2 p.Ala496Gly Uncertain significance ★★ ⚠ same type
NFE2L2 p.Arg34Gln Uncertain significance ★★ ⚠ same type
NFE2L2 p.Arg449Cys Uncertain significance ★★ ⚠ same type
NFE2L2 p.Arg569Cys Uncertain significance ★★ ⚠ same type
NFE2L2 p.Asn101Ser Uncertain significance ★★ ⚠ same type
NFE2L2 p.Asn225Ser 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/nfe2l2-p-pro233ser (accessed [today's date]).

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