Is ASPNAT p.Pro41Leu (c.122C>T) pathogenic?

ASPNAT p.Pro41Leu (c.122C>T) is classified Uncertain significance in ASPNAT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-08). AlphaMissense: likely benign (0.1988); Ultra-rare (popmax 0.0116%, eas).

How common is ASPNAT p.Pro41Leu (c.122C>T) in the general population?

ASPNAT p.Pro41Leu (c.122C>T) is ultra-rare (popmax 0.0116%, eas) (gnomAD).

What do computational predictors say about ASPNAT p.Pro41Leu (c.122C>T)?

AlphaMissense predicts likely benign (score 0.1988) — an in-silico prediction, not a clinical call.

ASPNAT p.Pro41Leu

c.122C>T · VCV3402751

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1988 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0116%, eas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1988	likely benign
REVEL	0.052	moderately benign-leaning
SaProt	LLR -8.05	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 3.8	GERP 0.058, phastCons 1
Regional constraint	o/e 1.01	unconstrained · MANE · 1,534 bp · p 0.84 · regional, not allelic
Overall
CADD	22.6	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 0.0116% East Asian · 1/8,588 alleles

Overall 0.000689% 1/145,122 alleles · ultra-rare

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: ASPNAT
Protein: p.Pro41Leu
Coding: c.122C>T
MANE Select: NM_178557
Type: single nucleotide variant
Location: chr4:2059633 (GRCh38)
Structure: AlphaFold pLDDT 81.36

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

Similar variants

ASPNAT c.541+8C>T Benign ★★ same type
ASPNAT p.Ala35= Likely benign ★★ same type
ASPNAT p.Gly263= Likely benign ★★ same type
ASPNAT p.Pro56= Likely benign ★★ same type
ASPNAT p.Ala125Thr Uncertain significance ★ ⚠ same type
ASPNAT p.Ala225Thr Uncertain significance ★ ⚠ same type
ASPNAT p.Ala22Val Uncertain significance ★ ⚠ same type
ASPNAT p.Ala255Thr 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/aspnat-p-pro41leu (accessed [today's date]).

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