Is AMN p.Pro444Ser (c.1330C>T) pathogenic?

AMN p.Pro444Ser (c.1330C>T) is classified Uncertain significance in AMN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-04-25). AlphaMissense: ambiguous (0.5429); Very rare (popmax 0.00171%, amr); Associated with Inborn genetic diseases.

What condition is associated with AMN p.Pro444Ser (c.1330C>T)?

AMN p.Pro444Ser (c.1330C>T) is associated with Inborn genetic diseases, Imerslund-Grasbeck syndrome (ClinVar).

How common is AMN p.Pro444Ser (c.1330C>T) in the general population?

AMN p.Pro444Ser (c.1330C>T) is very rare (popmax 0.00171%, amr) (gnomAD).

What do computational predictors say about AMN p.Pro444Ser (c.1330C>T)?

AlphaMissense predicts ambiguous (score 0.5429) — an in-silico prediction, not a clinical call.

AMN p.Pro444Ser

c.1330C>T · rs1354241478 · VCV1398618

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5429 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00171%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.5429	ambiguous
REVEL	0.775	moderately pathogenic-leaning
SaProt	LLR -9.64	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 6.7	GERP 1.3, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	24.0	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 0.00171% Admixed American · 1/58,528 alleles

Overall 0.000207% 3/1,447,068 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00171%	58,528
Remaining individualsnot grpmax-eligible	0.00162%	61,810
European (non-Finnish)	8.52e-05%	1,174,306

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.Pro444Ser
Coding: c.1330C>T
MANE Select: NM_030943
dbSNP: rs1354241478
Type: single nucleotide variant
Location: chr14:102930648 (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

Also linked: Imerslund-Grasbeck syndrome

Similar variants

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
AMN c.296-3C>T 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-pro444ser (accessed [today's date]).

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