Is AMBN p.Ala412Pro (c.1234G>C) pathogenic?

AMBN p.Ala412Pro (c.1234G>C) is classified Uncertain significance in AMBN (ClinVar, Single submitter, 1 submitter; last evaluated 2024-09-11). AlphaMissense: likely benign (0.1312); Absent from gnomAD v4.1.

How common is AMBN p.Ala412Pro (c.1234G>C) in the general population?

AMBN p.Ala412Pro (c.1234G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about AMBN p.Ala412Pro (c.1234G>C)?

AlphaMissense predicts likely benign (score 0.1312) — an in-silico prediction, not a clinical call.

AMBN p.Ala412Pro

c.1234G>C · VCV3534644

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1312 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1312	likely benign
REVEL	0.083	moderately benign-leaning
SaProt	LLR -5.97	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 1.1	GERP -3.5, phastCons 0.23
Regional constraint	o/e 1.04	unconstrained · MANE · 14 kb · p 0.31 · regional, not allelic
Overall
CADD	3.656	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: AMBN
Protein: p.Ala412Pro
Coding: c.1234G>C
MANE Select: NM_016519
Type: single nucleotide variant
Location: chr4:70606620 (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

Similar variants

AMBN p.Ser70Ter Uncertain significance ★★ same type
AMBN p.Gly268Arg Likely benign ★★ same type
AMBN p.His294Gln Benign/Likely benign ★★ same type
AMBN p.Leu354Pro Benign ★★ same type
AMBN p.Val378Ile Benign ★★ same type
AMBN c.295-2A>C Likely pathogenic ★ same type
AMBN c.15+1G>A Uncertain significance ★ same type
AMBN c.571-1G>C Conflicting classifications of pathogenicity ★ 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-ala412pro (accessed [today's date]).

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