Is A2ML1 p.Pro217Leu (c.650C>T) pathogenic?

A2ML1 p.Pro217Leu (c.650C>T) is classified Uncertain significance in A2ML1 (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-03-13). AlphaMissense: likely benign (0.2328); Ultra-rare (popmax 0.0164%, mid).

How common is A2ML1 p.Pro217Leu (c.650C>T) in the general population?

A2ML1 p.Pro217Leu (c.650C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about A2ML1 p.Pro217Leu (c.650C>T)?

AlphaMissense predicts likely benign (score 0.2328) — an in-silico prediction, not a clinical call.

A2ML1 p.Pro217Leu

c.650C>T · rs773797927 · VCV561682

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2328 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.2328	likely benign
REVEL	0.372	indeterminate
SaProt	LLR -13.48	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 2.7	GERP 0.5, phastCons 0.99
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	24.4	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 0.0164% Middle Eastern · 1/6,082 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.00112% 18/1,613,720 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,082
Admixed American	0.00667%	14,993
East Asian	0.00223%	44,876
South Asian	0.0022%	45,528
Remaining individualsnot grpmax-eligible	0.0016%	62,472
African / African-American	0.00134%	74,856
European (non-Finnish)	0.000678%	147,490

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.Pro217Leu
Coding: c.650C>T
MANE Select: NM_144670
dbSNP: rs773797927
Type: single nucleotide variant
Location: chr12:8836261 (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.Pro217= 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
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-pro217leu (accessed [today's date]).

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