Is AMBN p.Pro435= (c.1305C>T) pathogenic?

AMBN p.Pro435= (c.1305C>T) is classified Likely benign in AMBN (ClinVar, Single submitter, 1 submitter; last evaluated 2022-07-01). Very rare (popmax 0.00223%, eas).

How common is AMBN p.Pro435= (c.1305C>T) in the general population?

AMBN p.Pro435= (c.1305C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

AMBN p.Pro435=

c.1305C>T · rs201142712 · VCV2654797

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

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 0.15	GERP -2.1, phastCons 0.91
Overall
CADD	5.443	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,854 alleles

Filtering AF 0.00111% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0009%

Overall 0.00143% 23/1,613,848 alleles · very rare exomes 20/1,461,594 · genomes 3/152,254 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,854
European (non-Finnish)	0.0017%	58,993
Remaining individualsnot grpmax-eligible	0.0016%	62,492
African / African-American	0.00133%	75,044

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.Pro435=
Coding: c.1305C>T
MANE Select: NM_016519
dbSNP: rs201142712
Type: single nucleotide variant
Location: chr4:70606691 (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-pro435 (accessed [today's date]).

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