Is NFE2 p.Pro95Ser (c.283C>T) pathogenic?

NFE2 p.Pro95Ser (c.283C>T) is classified Uncertain significance in NFE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-29). AlphaMissense: likely benign (0.0691); Ultra-rare (popmax 0.0332%, mid).

How common is NFE2 p.Pro95Ser (c.283C>T) in the general population?

NFE2 p.Pro95Ser (c.283C>T) is ultra-rare (popmax 0.0332%, mid) (gnomAD).

What do computational predictors say about NFE2 p.Pro95Ser (c.283C>T)?

AlphaMissense predicts likely benign (score 0.0691) — an in-silico prediction, not a clinical call.

NFE2 p.Pro95Ser

c.283C>T · VCV4119356

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0691 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0332%, mid)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0691	likely benign
REVEL	0.019	moderately benign-leaning
SaProt	LLR -5.90	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 1.1	GERP -3.5, phastCons 0.49
Regional constraint	o/e 0.80	unconstrained · MANE · 2,871 bp · p 9.6e-06 · regional, not allelic
Overall
CADD	1.876	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 0.0332% Middle Eastern · 2/6,022 alleles

Filtering AF 0.00585% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00243%

Overall 0.00187% 30/1,604,040 alleles · ultra-rare exomes 28/1,451,904 · genomes 2/152,136 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0332%	3,011
Admixed American	0.00507%	19,705
European (non-Finnish)	0.00196%	51,077
Remaining individualsnot grpmax-eligible	0.00161%	62,106
African / African-American	0.00134%	74,708

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.Pro95Ser
Coding: c.283C>T
MANE Select: NM_001136023
Type: single nucleotide variant
Location: chr12:54293213 (GRCh38)
Gene constraint: LOEUF 0.798 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 67.50 · 1 PDB
Residue 95: the 'transactivation domain' region

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-pro95ser (accessed [today's date]).

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