Is AMN p.Thr277Ala (c.829A>G) pathogenic?

AMN p.Thr277Ala (c.829A>G) is classified Benign/Likely benign in AMN (ClinVar, Multiple submitters, 6 submitters; last evaluated 2026-01-31). AlphaMissense: likely benign (0.0637); Rare (popmax 0.916%, sas); Associated with Imerslund-Grasbeck syndrome type 2.

What condition is associated with AMN p.Thr277Ala (c.829A>G)?

AMN p.Thr277Ala (c.829A>G) is associated with Imerslund-Grasbeck syndrome type 2, Imerslund-Grasbeck syndrome (ClinVar).

How common is AMN p.Thr277Ala (c.829A>G) in the general population?

AMN p.Thr277Ala (c.829A>G) is rare (popmax 0.916%, sas) (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.Thr277Ala (c.829A>G)?

AlphaMissense predicts likely benign (score 0.0637) — an in-silico prediction, not a clinical call.

AMN p.Thr277Ala

c.829A>G · rs146499374 · VCV463391

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 6 submitters

AlphaMissense

likely benign

0.0637 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.916%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Imerslund-Grasbeck syndrome type 2

Computational evidence

Protein change
AlphaMissense	0.0637	likely benign
REVEL	0.172	moderately benign-leaning
SaProt	LLR -5.70	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.28	GERP -2
Regional constraint	o/e 1.06	unconstrained · MANE · 7,988 bp · p 0.14 · regional, not allelic
Overall
CADD	0.24	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 0.916% South Asian · 770/84,062 alleles

Filtering AF 0.862% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.841%

Overall 0.629% 9,755/1,550,414 alleles · rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.916%	109
Middle Eastern	0.825%	121
European (non-Finnish)	0.712%	141
Remaining individualsnot grpmax-eligible	0.606%	165
Admixed American	0.446%	224
Finnishnot grpmax-eligible	0.128%	784
African / African-American	0.123%	813
Ashkenazi Jewishnot grpmax-eligible	0.0593%	1,685
East Asian	0.00488%	20,474

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.Thr277Ala
Coding: c.829A>G
MANE Select: NM_030943
dbSNP: rs146499374
Type: single nucleotide variant
Location: chr14:102929723 (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 277: an α-helix

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

Disease context

Imerslund-Grasbeck syndrome type 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: Imerslund-Grasbeck syndrome

For Imerslund-Gräsbeck syndrome (Orphanet):

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

Similar variants

AMN p.Thr277= 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-thr277ala (accessed [today's date]).

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