Is A2ML1 p.Pro21Ala (c.61C>G) pathogenic?

A2ML1 p.Pro21Ala (c.61C>G) is classified Conflicting classifications of pathogenicity in A2ML1 (ClinVar, Conflicting submitters, 2 submitters; last evaluated 2026-06-12). AlphaMissense: likely benign (0.1819); Ultra-rare (popmax 0.0681%, sas).

How common is A2ML1 p.Pro21Ala (c.61C>G) in the general population?

A2ML1 p.Pro21Ala (c.61C>G) is ultra-rare (popmax 0.0681%, sas) (gnomAD).

What do computational predictors say about A2ML1 p.Pro21Ala (c.61C>G)?

AlphaMissense predicts likely benign (score 0.1819) — an in-silico prediction, not a clinical call.

A2ML1 p.Pro21Ala

c.61C>G · rs749520022 · VCV760642

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1819 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0681%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1819	likely benign
REVEL	0.207	benign-leaning
SaProt	LLR -7.03	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 4.7	GERP 0.74, phastCons 0.96
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	24.8	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 0.0681% South Asian · 62/91,072 alleles

Filtering AF 0.0544% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0495%

Overall 0.00446% 72/1,614,008 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0681%	1,469
Middle Eastern	0.0164%	6,084
Remaining individualsnot grpmax-eligible	0.008%	12,496
Finnishnot grpmax-eligible	0.00156%	64,042
African / African-American	0.00133%	74,940
European (non-Finnish)	0.000169%	589,984

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.Pro21Ala
Coding: c.61C>G
MANE Select: NM_144670
dbSNP: rs749520022
Type: single nucleotide variant
Location: chr12:8822712 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB

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

Similar variants

A2ML1 p.Pro21Thr 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
A2ML1 c.*1+1G>A Uncertain significance ★★ same type
A2ML1 p.Ala1002Val 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-pro21ala (accessed [today's date]).

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