Is AMBN p.Ala441= (c.1323A>G) pathogenic?

AMBN p.Ala441= (c.1323A>G) is classified Benign in AMBN (ClinVar, No assertion criteria, 1 submitter; last evaluated 2024-03-13). Common (popmax 59.9%, afr) — too common for a highly-penetrant pathogenic allele; Associated with AMBN-related disorder.

What condition is associated with AMBN p.Ala441= (c.1323A>G)?

AMBN p.Ala441= (c.1323A>G) is associated with AMBN-related disorder (ClinVar).

AMBN p.Ala441=

Q: How common is AMBN p.Ala441= (c.1323A>G) in the general population?

AMBN p.Ala441= (c.1323A>G) is common (popmax 59.9%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.1323A>G · rs7680880 · VCV3059474

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 59.9%, afr) — too common for a highly-penetrant pathogenic allele

Conditions

AMBN-related disorder

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -4.8	GERP -3.5
Overall
CADD	0.075	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 59.9% African / African-American · 44,839/74,880 alleles

Filtering AF 59.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 59.2%

Overall 10.8% 173,841/1,612,720 alleles · common

Ancestry group	Frequency	1 in
African / African-Americangrpmax	59.9%	2
South Asian	15.9%	6
East Asian	15%	7
Middle Eastern	13.5%	7
Remaining individualsnot grpmax-eligible	12.7%	8
Admixed American	11.3%	9
Finnishnot grpmax-eligible	10.4%	10
Amishnot grpmax-eligible	9.32%	11
Ashkenazi Jewishnot grpmax-eligible	9.01%	11
European (non-Finnish)	7.03%	14

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: AMBN
Protein: p.Ala441=
Coding: c.1323A>G
MANE Select: NM_016519
dbSNP: rs7680880
Type: single nucleotide variant
Location: chr4:70606709 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 44.05

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

Disease context

AMBN-related disorder

Similar variants

AMBN c.532-9G>C Likely benign same condition
AMBN c.753+3A>G Likely benign same condition
AMBN p.Ala255Val Benign same condition
AMBN p.Gln219= Benign same condition
AMBN p.Gly78Val Benign ⚠ same condition
AMBN p.Val244Met Benign same condition
AMBN p.Gly180del Benign same condition
AMBN p.Ser70Ter Uncertain significance ★★ same type

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/ambn-p-ala441 (accessed [today's date]).

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