Is AMN p.Cys250Trp (c.750T>G) pathogenic?

AMN p.Cys250Trp (c.750T>G) is classified Uncertain significance in AMN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-12-16). AlphaMissense: likely pathogenic (0.8927); Ultra-rare (popmax 0.0171%, eas); Associated with Inborn genetic diseases.

What condition is associated with AMN p.Cys250Trp (c.750T>G)?

AMN p.Cys250Trp (c.750T>G) is associated with Inborn genetic diseases (ClinVar).

How common is AMN p.Cys250Trp (c.750T>G) in the general population?

AMN p.Cys250Trp (c.750T>G) is ultra-rare (popmax 0.0171%, eas) (gnomAD).

What do computational predictors say about AMN p.Cys250Trp (c.750T>G)?

AlphaMissense predicts likely pathogenic (score 0.8927) — an in-silico prediction, not a clinical call.

AMN p.Cys250Trp

c.750T>G · rs1308282018 · VCV3116065

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely pathogenic

0.8927 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0171%, eas)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.8927	likely pathogenic · top 5% in AMN
REVEL	0.674	pathogenic-leaning
SaProt	LLR -15.12	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.041	GERP -0.17, phastCons 0.84
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	23.5	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 0.0171% East Asian · 7/40,886 alleles

Filtering AF 0.00799% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00565%

Overall 0.000846% 13/1,537,406 alleles · ultra-rare exomes 11/1,385,254 · genomes 2/152,152 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0171%	5,841
European (non-Finnish)	0.000523%	191,068

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.Cys250Trp
Coding: c.750T>G
MANE Select: NM_030943
dbSNP: rs1308282018
Type: single nucleotide variant
Location: chr14:102929526 (GRCh38)
Gene constraint: LOEUF 1.446 · pLI <0.01 · ClinGen HI gene assoc. with recessive phenotype (gnomAD)
Structure: AlphaFold pLDDT 80.78 · 1 PDB
Residue 250: a disulfide bond; the vwfc domain

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.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.Gln288His Uncertain significance ★★ ⚠ same condition
AMN p.Pro444Ser Uncertain significance ★★ ⚠ same condition
AMN p.Ser437Asn Uncertain significance ★★ ⚠ same condition
AMN p.Val442Ile 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-cys250trp (accessed [today's date]).

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