Is NFE2L2 p.Ser99Pro (c.295T>C) pathogenic?

NFE2L2 p.Ser99Pro (c.295T>C) is classified Uncertain significance in NFE2L2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-02-07). AlphaMissense: likely benign (0.0682); Ultra-rare (popmax 0.0147%, afr).

How common is NFE2L2 p.Ser99Pro (c.295T>C) in the general population?

NFE2L2 p.Ser99Pro (c.295T>C) is ultra-rare (popmax 0.0147%, afr) (gnomAD).

What do computational predictors say about NFE2L2 p.Ser99Pro (c.295T>C)?

AlphaMissense predicts likely benign (score 0.0682) — an in-silico prediction, not a clinical call.

NFE2L2 p.Ser99Pro

c.295T>C · VCV3713545

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0682 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0147%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0682	likely benign
REVEL	0.082	moderately benign-leaning
SaProt	LLR -6.65	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 2.3	GERP 0.73, phastCons 0.81
Regional constraint	o/e 0.60	unconstrained · MANE · 31 kb · p 9.2e-07 · regional, not allelic
Overall
CADD	17.57	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 0.0147% African / African-American · 11/75,052 alleles

Filtering AF 0.00814% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00632%

Overall 0.000681% 11/1,614,218 alleles · ultra-rare exomes 3/1,461,878 · genomes 8/152,340 · 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: NFE2L2
Protein: p.Ser99Pro
Coding: c.295T>C
MANE Select: NM_006164
Type: single nucleotide variant
Location: chr2:177234022 (GRCh38)
Gene constraint: LOEUF 0.575 · pLI 0.50 (gnomAD)
Structure: AlphaFold pLDDT 61.72 · 23 PDB
Residue 99: a UniProt-annotated variant site (in)

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

Similar variants

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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
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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-ser99pro (accessed [today's date]).

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