Is A2ML1 p.Ser717Pro (c.2149T>C) pathogenic?

A2ML1 p.Ser717Pro (c.2149T>C) is classified Uncertain significance in A2ML1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-10-11). AlphaMissense: likely benign (0.0616); Very rare (popmax 0.00267%, afr).

How common is A2ML1 p.Ser717Pro (c.2149T>C) in the general population?

A2ML1 p.Ser717Pro (c.2149T>C) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about A2ML1 p.Ser717Pro (c.2149T>C)?

AlphaMissense predicts likely benign (score 0.0616) — an in-silico prediction, not a clinical call.

A2ML1 p.Ser717Pro

c.2149T>C · rs1238150217 · VCV2857585

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0616 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0616	likely benign
REVEL	0.014	strongly benign-leaning
SaProt	LLR -6.24	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 -3.4	GERP -0.03
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	1.798	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00267% African / African-American · 2/74,768 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000124% 2/1,612,126 alleles · very rare

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.Ser717Pro
Coding: c.2149T>C
MANE Select: NM_144670
dbSNP: rs1238150217
Type: single nucleotide variant
Location: chr12:8850189 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 717: a disulfide bond; the 'bait region' region; a UniProt-annotated variant site (risk factor for otitis media)

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

Similar variants

A2ML1 p.Ser717Ter 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-ser717pro (accessed [today's date]).

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