Is AMN p.Val66Ala (c.197T>C) pathogenic?

AMN p.Val66Ala (c.197T>C) is classified Uncertain significance in AMN (ClinVar, Multiple submitters, 3 submitters; last evaluated 2025-02-06). AlphaMissense: ambiguous (0.3731); Very rare (popmax 0.00898%, nfe); Associated with Imerslund-Grasbeck syndrome.

What condition is associated with AMN p.Val66Ala (c.197T>C)?

AMN p.Val66Ala (c.197T>C) is associated with Imerslund-Grasbeck syndrome, Imerslund-Grasbeck syndrome type 2 (ClinVar).

How common is AMN p.Val66Ala (c.197T>C) in the general population?

AMN p.Val66Ala (c.197T>C) is very rare (popmax 0.00898%, 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.Val66Ala (c.197T>C)?

AlphaMissense predicts ambiguous (score 0.3731) — an in-silico prediction, not a clinical call.

AMN p.Val66Ala

c.197T>C · rs371713937 · VCV1414197

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 3 submitters

AlphaMissense

ambiguous

0.3731 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00898%, nfe)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Imerslund-Grasbeck syndrome

Computational evidence

Protein change
AlphaMissense	0.3731	ambiguous
REVEL	0.171	moderately benign-leaning
SaProt	LLR -9.46	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 1.1, phastCons 0.98
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	18.39	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 0.00898% European (non-Finnish) · 106/1,180,006 alleles

Filtering AF 0.00757% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00706%

Overall 0.00707% 114/1,613,074 alleles · very rare exomes 104/1,460,948 · genomes 10/152,126 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00898%	11,132
Remaining individualsnot grpmax-eligible	0.008%	12,495
East Asian	0.00223%	44,878
Admixed American	0.00167%	60,002
Finnishnot grpmax-eligible	0.00158%	63,128

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.Val66Ala
Coding: c.197T>C
MANE Select: NM_030943
dbSNP: rs371713937
Type: single nucleotide variant
Location: chr14:102923969 (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 66: a β-strand

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

Also linked: Imerslund-Grasbeck syndrome type 2

For Imerslund-Gräsbeck syndrome (Orphanet):

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

Similar variants

AMN p.Val66Ile 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-val66ala (accessed [today's date]).

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