Is A2ML1 p.Pro568= (c.1704C>T) pathogenic?

A2ML1 p.Pro568= (c.1704C>T) is classified Likely benign in A2ML1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-04-24). Very rare (popmax 0.00223%, eas).

How common is A2ML1 p.Pro568= (c.1704C>T) in the general population?

A2ML1 p.Pro568= (c.1704C>T) is very rare (popmax 0.00223%, eas) (gnomAD).

A2ML1 p.Pro568=

c.1704C>T · VCV4053964

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 -0.55	GERP -3.6, phastCons 0.007
Overall
CADD	0.926	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00223% East Asian · 1/44,772 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000274% 4/1,459,780 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,772
European (non-Finnish)	0.000254%	393,065

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.Pro568=
Coding: c.1704C>T
MANE Select: NM_144670
Type: single nucleotide variant
Location: chr12:8847569 (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.Pro568Leu Uncertain significance ★★ ⚠ same residue
A2ML1 p.Pro568Ala Uncertain significance ★ ⚠ 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-pro568 (accessed [today's date]).

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