Is A2ML1 p.Pro86Ser (c.256C>T) pathogenic?

A2ML1 p.Pro86Ser (c.256C>T) is classified Uncertain significance in A2ML1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-01-20). AlphaMissense: ambiguous (0.4891); Ultra-rare (popmax 0.0356%, eas); Associated with A2ML1-related disorder.

What condition is associated with A2ML1 p.Pro86Ser (c.256C>T)?

A2ML1 p.Pro86Ser (c.256C>T) is associated with A2ML1-related disorder (ClinVar).

How common is A2ML1 p.Pro86Ser (c.256C>T) in the general population?

A2ML1 p.Pro86Ser (c.256C>T) is ultra-rare (popmax 0.0356%, eas) (gnomAD).

What do computational predictors say about A2ML1 p.Pro86Ser (c.256C>T)?

AlphaMissense predicts ambiguous (score 0.4891) — an in-silico prediction, not a clinical call.

A2ML1 p.Pro86Ser

c.256C>T · rs766201825 · VCV967222

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.4891 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0356%, eas)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Conditions

A2ML1-related disorder

Computational evidence

Protein change
AlphaMissense	0.4891	ambiguous
REVEL	0.049	moderately benign-leaning
SaProt	LLR -11.13	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6.2	GERP 0.77, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 52 kb · p 0.02 · regional, not allelic
Overall
CADD	22.5	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 0.0356% East Asian · 16/44,882 alleles

Filtering AF 0.0223% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0182%

Overall 0.0031% 50/1,613,820 alleles · ultra-rare exomes 38/1,461,516 · genomes 12/152,304 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.0356%	2,805
South Asian	0.0264%	3,792
Remaining individualsnot grpmax-eligible	0.0144%	6,943
European (non-Finnish)	8.48e-05%	1,179,878

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.Pro86Ser
Coding: c.256C>T
MANE Select: NM_144670
dbSNP: rs766201825
Type: single nucleotide variant
Location: chr12:8823729 (GRCh38)
Gene constraint: LOEUF 0.953 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.61 · 5 PDB
Residue 86: an α-helix

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

Disease context

A2ML1-related disorder

Similar variants

A2ML1 p.Pro86Leu Uncertain significance ★★ ⚠ same residue
A2ML1 c.1834-1G>T Uncertain significance ★★ same condition
A2ML1 p.Arg1001Trp Uncertain significance ★★ ⚠ same condition
A2ML1 p.Asn1427Ser Uncertain significance ★★ ⚠ same condition
A2ML1 p.Gln255Pro Uncertain significance ★★ ⚠ same condition
A2ML1 p.Gly544Ser Uncertain significance ★★ ⚠ same condition
A2ML1 p.Leu282Ile Uncertain significance ★★ ⚠ same condition
A2ML1 p.Met1116Leu Uncertain significance ★★ ⚠ same condition

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-pro86ser (accessed [today's date]).

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