Is NCL p.Ala103Val (c.308C>T) pathogenic?

NCL p.Ala103Val (c.308C>T) is classified Uncertain significance in NCL (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-16). AlphaMissense: likely benign (0.0827); Absent from gnomAD v4.1.

How common is NCL p.Ala103Val (c.308C>T) in the general population?

NCL p.Ala103Val (c.308C>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about NCL p.Ala103Val (c.308C>T)?

AlphaMissense predicts likely benign (score 0.0827) — an in-silico prediction, not a clinical call.

NCL p.Ala103Val

c.308C>T · VCV3403443

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0827 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0827	likely benign
REVEL	0.067	moderately benign-leaning
SaProt	LLR -7.41	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 5.7	GERP 0.72, phastCons 1
Regional constraint	o/e 1.03	unconstrained · MANE · 6,682 bp · p 0.41 · regional, not allelic
Overall
CADD	18.95	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

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: NCL
Protein: p.Ala103Val
Coding: c.308C>T
MANE Select: NM_005381
Type: single nucleotide variant
Location: chr2:231461845 (GRCh38)
Gene constraint: LOEUF 0.102 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 62.84 · 4 PDB
Residue 103: the 'disordered' region; the '8 x 8 aa tandem repeats of x-t-p-x-k-k-x-x' region

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

Similar variants

NCL p.Gly662Ser Uncertain significance ★★ same type
NCL p.Ala629= Benign ★★ same type
NCL p.Asp535= Benign ★★ same type
NCL p.Glu196Asp Benign ★★ same type
NCL p.Glu585= Benign ★★ same type
NCL p.Lys116Thr Benign ★★ ⚠ same type
NUCLEOLIN p.Ser328= Likely benign ★★ same type
NCL p.Ala134Ser 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/ncl-p-ala103val (accessed [today's date]).

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