Is AMN p.Val25Asp (c.74T>A) pathogenic?

AMN p.Val25Asp (c.74T>A) is classified Uncertain significance in AMN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-30). AlphaMissense: ambiguous (0.3921); Very rare (popmax 0.00167%, amr); Associated with Inborn genetic diseases.

What condition is associated with AMN p.Val25Asp (c.74T>A)?

AMN p.Val25Asp (c.74T>A) is associated with Inborn genetic diseases (ClinVar).

How common is AMN p.Val25Asp (c.74T>A) in the general population?

AMN p.Val25Asp (c.74T>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about AMN p.Val25Asp (c.74T>A)?

AlphaMissense predicts ambiguous (score 0.3921) — an in-silico prediction, not a clinical call.

AMN p.Val25Asp

c.74T>A · VCV4092293

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3921 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.3921	ambiguous
REVEL	0.694	pathogenic-leaning
SaProt	LLR -8.67	tolerated
⇒ REVEL calls this damaging; SaProt does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.4	GERP 1.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	24.1	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

Grpmax group 0.00167% Admixed American · 1/60,012 alleles

Overall 0.000657% 1/152,136 alleles · very 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: AMN
Protein: p.Val25Asp
Coding: c.74T>A
MANE Select: NM_030943
Type: single nucleotide variant
Location: chr14:102923741 (GRCh38)
Gene constraint: LOEUF 1.446 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.78 · 1 PDB

Full AMN 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

AMN p.Val25Ala Uncertain significance ★ ⚠ same residue
AMN p.Val25= Likely benign ★ same residue
AMN p.Ala238Thr Uncertain significance ★★ ⚠ same condition
AMN p.Ala44Thr Uncertain significance ★★ ⚠ same condition
AMN p.Arg271Trp Uncertain significance ★★ ⚠ same condition
AMN p.Arg424Gly Uncertain significance ★★ ⚠ same condition
AMN p.Cys250Trp Uncertain significance ★★ ⚠ same condition
AMN p.Gln288His 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/amn-p-val25asp (accessed [today's date]).

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