Is A2ML1 p.Cys970Tyr (c.2909G>A) pathogenic?

A2ML1 p.Cys970Tyr (c.2909G>A) is classified Benign/Likely benign in A2ML1 (ClinVar, Multiple submitters, 5 submitters; last evaluated 2026-02-04). AlphaMissense: likely pathogenic (0.6729); Common (popmax 27.3%, mid) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about A2ML1 p.Cys970Tyr (c.2909G>A)?

AlphaMissense predicts likely pathogenic (score 0.6729) — an in-silico prediction, not a clinical call.

A2ML1 p.Cys970Tyr

Q: How common is A2ML1 p.Cys970Tyr (c.2909G>A) in the general population?

A2ML1 p.Cys970Tyr (c.2909G>A) is common (popmax 27.3%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.2909G>A · rs1558526 · VCV384673

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 5 submitters

AlphaMissense

likely pathogenic

0.6729 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 27.3%, mid) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.6729	likely pathogenic
REVEL	0.637	indeterminate
SaProt	LLR -7.25	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.6	GERP 0.94, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	23.9	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 27.3% Middle Eastern · 1,426/5,228 alleles

Filtering AF 26.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 25.6%

Overall 22.7% 366,375/1,612,900 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	40.2%	2
Middle Easterngrpmax	27.3%	4
European (non-Finnish)	25.6%	4
Remaining individualsnot grpmax-eligible	22.5%	4
Amishnot grpmax-eligible	17.5%	6
Finnishnot grpmax-eligible	16%	6
Admixed American	15.3%	7
South Asian	15.3%	7
African / African-American	4.33%	23
East Asian	0.0624%	1,603

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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.Cys970Tyr
Coding: c.2909G>A
MANE Select: NM_144670
dbSNP: rs1558526
Type: single nucleotide variant
Location: chr12:8857224 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 970: a disulfide bond; a cross-link site; a UniProt-annotated variant site (risk factor for otitis media); a UniProt-annotated variant site (in)

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

Similar variants

A2ML1 p.Cys970Arg 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-cys970tyr (accessed [today's date]).

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