Is A2ML1 p.Pro568Leu (c.1703C>T) pathogenic?

A2ML1 p.Pro568Leu (c.1703C>T) is classified Uncertain significance in A2ML1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-07-17). AlphaMissense: likely benign (0.1086); Very rare (popmax 0.00223%, eas).

How common is A2ML1 p.Pro568Leu (c.1703C>T) in the general population?

A2ML1 p.Pro568Leu (c.1703C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about A2ML1 p.Pro568Leu (c.1703C>T)?

AlphaMissense predicts likely benign (score 0.1086) — an in-silico prediction, not a clinical call.

A2ML1 p.Pro568Leu

c.1703C>T · rs377555263 · VCV2449319

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1086 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1086	likely benign
REVEL	0.244	benign-leaning
SaProt	LLR -12.61	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 3.8	GERP -2.6, phastCons 0.81
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	17.49	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 0.00223% East Asian · 1/44,756 alleles

Overall 0.000206% 3/1,459,638 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,756
Admixed American	0.00168%	59,598
European (non-Finnish)	8.48e-05%	1,179,156

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: A2ML1
Protein: p.Pro568Leu
Coding: c.1703C>T
MANE Select: NM_144670
dbSNP: rs377555263
Type: single nucleotide variant
Location: chr12:8847568 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 568: a UniProt-annotated variant site (risk factor for otitis media); a β-strand

Full A2ML1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

A2ML1 p.Pro568Arg Uncertain significance ★★ ⚠ same residue
A2ML1 p.Pro568Ala Uncertain significance ★ ⚠ same residue
A2ML1 p.Pro568= Likely benign ★ same residue
A2ML1 c.1834-1G>T Uncertain significance ★★ same type
A2ML1 c.3264+4C>T Uncertain significance ★★ same type
A2ML1 c.3933+4A>G Uncertain significance ★★ same type
A2ML1 c.409+1G>A Uncertain significance ★★ same type
A2ML1 c.4221+2T>C 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/a2ml1-p-pro568leu (accessed [today's date]).

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