Is AMN p.Cys234Phe (c.701G>T) pathogenic?

AMN p.Cys234Phe (c.701G>T) is classified Likely pathogenic in AMN (ClinVar, No assertion criteria, 1 submitter). AlphaMissense: likely pathogenic (0.7177); Very rare (popmax 0.00882%, nfe); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with AMN p.Cys234Phe (c.701G>T)?

AMN p.Cys234Phe (c.701G>T) is associated with Imerslund-Grasbeck syndrome (ClinVar).

How common is AMN p.Cys234Phe (c.701G>T) in the general population?

AMN p.Cys234Phe (c.701G>T) is very rare (popmax 0.00882%, nfe) (gnomAD).

How is Imerslund-Gräsbeck syndrome inherited?

Typically Autosomal recessive (Orphanet). A genetic counselor can assess individual risk for a family.

What do computational predictors say about AMN p.Cys234Phe (c.701G>T)?

AlphaMissense predicts likely pathogenic (score 0.7177) — an in-silico prediction, not a clinical call.

AMN p.Cys234Phe

c.701G>T · rs386834176 · VCV56758

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7177 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00882%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Imerslund-Grasbeck syndrome

Computational evidence

Protein change
AlphaMissense	0.7177	likely pathogenic ✓ concordant with ClinVar
REVEL	0.781	moderately pathogenic-leaning
SaProt	LLR -14.68	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 7.6	GERP 0.93, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	24.8	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 0.00882% European (non-Finnish) · 101/1,145,238 alleles

Filtering AF 0.00738% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00688%

Overall 0.00747% 103/1,379,430 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00882%	11,339
Remaining individualsnot grpmax-eligible	0.00168%	59,684
African / African-American	0.00137%	72,950

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.Cys234Phe
Coding: c.701G>T
MANE Select: NM_030943
dbSNP: rs386834176
Type: single nucleotide variant
Location: chr14:102929477 (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 234: a disulfide bond; a UniProt-annotated variant site (in igs2; loss of interaction with cubn; strongly reduced cubn expression at the cell surface); an α-helix; the vwfc domain

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

Disease context

Imerslund-Grasbeck syndrome — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Imerslund-Gräsbeck syndrome (Orphanet):

Inheritance: Autosomal recessive
Onset: Childhood
Prevalence: 1-9 / 1 000 000 (Finland)

Similar variants

AMN p.Cys234= Likely benign ★ same residue
AMN c.208-1G>C Pathogenic/Likely pathogenic ★★ same condition
AMN c.296-1G>A Likely pathogenic ★★ same condition
AMN c.44-1G>A Likely pathogenic ★★ same condition
AMN c.760+1G>A Likely pathogenic ★★ same condition
AMN c.844-1G>C Likely pathogenic ★★ same condition
AMN p.Thr41Ile Likely pathogenic ★★ ⚠ same condition
AMN p.Trp391Ter Pathogenic/Likely pathogenic ★★ 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-cys234phe (accessed [today's date]).

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