Is AMBN p.Ala255Val (c.764C>T) pathogenic?

AMBN p.Ala255Val (c.764C>T) is classified Benign in AMBN (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-03-21). AlphaMissense: likely benign (0.1766); Common (popmax 14.3%, afr) — too common for a highly-penetrant pathogenic allele; Associated with AMBN-related disorder.

What condition is associated with AMBN p.Ala255Val (c.764C>T)?

AMBN p.Ala255Val (c.764C>T) is associated with AMBN-related disorder (ClinVar).

What do computational predictors say about AMBN p.Ala255Val (c.764C>T)?

AlphaMissense predicts likely benign (score 0.1766) — an in-silico prediction, not a clinical call.

AMBN p.Ala255Val

Q: How common is AMBN p.Ala255Val (c.764C>T) in the general population?

AMBN p.Ala255Val (c.764C>T) is common (popmax 14.3%, afr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.764C>T · rs7439186 · VCV3056421

Benign No assertion criteria

Classification

Benign

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1766 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 14.3%, afr) — too common for a highly-penetrant pathogenic allele

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

AMBN-related disorder

Computational evidence

Protein change
AlphaMissense	0.1766	likely benign
REVEL	0.102	moderately benign-leaning
SaProt	LLR -6.66	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 0.86	GERP -3, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 14 kb · p 0.31 · regional, not allelic
Overall
CADD	19.04	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 14.3% African / African-American · 10,685/74,952 alleles

Filtering AF 14% ClinGen BA1/BS1 input FAF95, joint · FAF99 13.9%

Overall 7.26% 117,082/1,613,484 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	14.6%	7
African / African-Americangrpmax	14.3%	7
Middle Eastern	13.7%	7
East Asian	12.9%	8
South Asian	11.3%	9
Amishnot grpmax-eligible	9.54%	10
Remaining individualsnot grpmax-eligible	8.47%	12
Admixed American	7.87%	13
Finnishnot grpmax-eligible	6.61%	15
European (non-Finnish)	6%	17

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Ala255Val
Coding: c.764C>T
MANE Select: NM_016519
dbSNP: rs7439186
Type: single nucleotide variant
Location: chr4:70603887 (GRCh38)
Gene constraint: LOEUF 1.345 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 44.05
Residue 255: a UniProt-annotated variant site (in)

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.Ala441= 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-ala255val (accessed [today's date]).

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