Is A2ML1 p.Thr995= (c.2985G>A) pathogenic?

A2ML1 p.Thr995= (c.2985G>A) is classified Likely benign in A2ML1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2026-01-12). Rare (popmax 0.82%, mid).

How common is A2ML1 p.Thr995= (c.2985G>A) in the general population?

A2ML1 p.Thr995= (c.2985G>A) is rare (popmax 0.82%, mid) (gnomAD).

A2ML1 p.Thr995=

c.2985G>A · rs773450242 · VCV241898

Likely benign Multiple submitters

Classification

Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.82%, mid)

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 -5.9	GERP -3.7
Overall
CADD	2.324	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.82% Middle Eastern · 49/5,978 alleles

Filtering AF 0.637% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.572%

Overall 0.0118% 191/1,613,828 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.82%	122
Ashkenazi Jewishnot grpmax-eligible	0.247%	406
East Asian	0.0134%	7,482
Remaining individualsnot grpmax-eligible	0.0128%	7,810
European (non-Finnish)	0.00441%	22,692
Admixed American	0.00167%	59,988
African / African-American	0.00134%	74,878
South Asian	0.0011%	91,058

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.Thr995=
Coding: c.2985G>A
MANE Select: NM_144670
dbSNP: rs773450242
Type: single nucleotide variant
Location: chr12:8857300 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 995: a disulfide bond; 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.Thr995Met Conflicting classifications of pathogenicity ★ ⚠ 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-thr995 (accessed [today's date]).

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