Is NFE2 p.Pro5Thr (c.13C>A) pathogenic?

NFE2 p.Pro5Thr (c.13C>A) is classified Uncertain significance in NFE2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-02). AlphaMissense: ambiguous (0.4379); Absent from gnomAD v4.1.

How common is NFE2 p.Pro5Thr (c.13C>A) in the general population?

NFE2 p.Pro5Thr (c.13C>A) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NFE2 p.Pro5Thr (c.13C>A)?

AlphaMissense predicts ambiguous (score 0.4379) — an in-silico prediction, not a clinical call.

NFE2 p.Pro5Thr

c.13C>A · VCV3919297

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.4379 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.4379	ambiguous
REVEL	0.123	moderately benign-leaning
SaProt	LLR -7.14	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 6.5	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	20.4	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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: NFE2
Protein: p.Pro5Thr
Coding: c.13C>A
MANE Select: NM_001136023
Type: single nucleotide variant
Location: chr12:54295236 (GRCh38)
Gene constraint: LOEUF 0.798 · pLI 0.02 (gnomAD)
Structure: AlphaFold pLDDT 67.50 · 1 PDB
Residue 5: the 'transactivation domain' region; the 'required for interaction with mapk8' 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-pro5thr (accessed [today's date]).

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