Is NT5E p.Ser396Pro (c.1186T>C) pathogenic?

NT5E p.Ser396Pro (c.1186T>C) is classified Uncertain significance in NT5E (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-21). AlphaMissense: likely pathogenic (0.936); Ultra-rare (popmax 0.02%, amr); Associated with Inborn genetic diseases.

What condition is associated with NT5E p.Ser396Pro (c.1186T>C)?

NT5E p.Ser396Pro (c.1186T>C) is associated with Inborn genetic diseases (ClinVar).

How common is NT5E p.Ser396Pro (c.1186T>C) in the general population?

NT5E p.Ser396Pro (c.1186T>C) is ultra-rare (popmax 0.02%, amr) (gnomAD).

What do computational predictors say about NT5E p.Ser396Pro (c.1186T>C)?

AlphaMissense predicts likely pathogenic (score 0.936) — an in-silico prediction, not a clinical call.

NT5E p.Ser396Pro

c.1186T>C · rs566262245 · VCV2400574

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.936 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.02%, amr)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.936	likely pathogenic
REVEL	0.357	indeterminate
SaProt	LLR -11.92	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.6	GERP 2.1, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 44 kb · p 0.13 · regional, not allelic
Overall
CADD	23.8	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.02% Admixed American · 12/60,010 alleles

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

Overall 0.0018% 29/1,613,738 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.02%	5,001
Remaining individualsnot grpmax-eligible	0.0064%	15,623
European (non-Finnish)	0.0011%	90,750

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: NT5E
Protein: p.Ser396Pro
Coding: c.1186T>C
MANE Select: NM_002526
dbSNP: rs566262245
Type: single nucleotide variant
Location: chr6:85489575 (GRCh38)
Gene constraint: LOEUF 1.254 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 91.95 · 52 PDB

Full NT5E gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

NT5E p.Ser396Leu Uncertain significance ★ ⚠ same residue
NT5E p.Ala10Pro Uncertain significance ★ ⚠ same condition
NT5E p.Ala151Pro Uncertain significance ★ ⚠ same condition
NT5E p.Ala151Thr Uncertain significance ★ ⚠ same condition
NT5E p.Ala15Gly Uncertain significance ★ ⚠ same condition
NT5E p.Ala260Pro Uncertain significance ★ ⚠ same condition
NT5E p.Ala280Ser Uncertain significance ★ ⚠ same condition
NT5E p.Ala5Thr Uncertain significance ★ ⚠ same condition

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/nt5e-p-ser396pro (accessed [today's date]).

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