Is A2ML1 c.855+237C>T pathogenic?

A2ML1 c.855+237C>T is classified Benign in A2ML1 (ClinVar, Single submitter, 1 submitter; last evaluated 2018-06-26). Common (popmax 36.8%, nfe) — too common for a highly-penetrant pathogenic allele.

A2ML1 c.855+237C>T

Q: How common is A2ML1 c.855+237C>T in the general population?

A2ML1 c.855+237C>T is common (popmax 36.8%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs11047514 · VCV1225391

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 36.8%, nfe) — too common for a highly-penetrant pathogenic allele

Computational evidence

Protein change
Missense predictors do not apply to this variant type.
Splicing
Splice region	donor +237	deep intronic (+237 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Overall
CADD	2.917	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 36.8% European (non-Finnish) · 24,912/67,760 alleles

Filtering AF 36.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 36.2%

Overall 26.7% 40,228/150,768 alleles · common

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	43.2%	2
Amishnot grpmax-eligible	38.8%	3
European (non-Finnish)grpmax	36.8%	3
Middle Eastern	35.4%	3
Remaining individualsnot grpmax-eligible	31.1%	3
Finnishnot grpmax-eligible	27.6%	4
Admixed American	25.5%	4
South Asian	18.5%	5
African / African-American	12.5%	8
East Asian	0.392%	255

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
Coding: c.855+237C>T
MANE Select: NM_144670
dbSNP: rs11047514
Type: single nucleotide variant
Location: chr12:8837803 (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 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
A2ML1 p.Ala1039Val 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-c-855-plus-237c-t (accessed [today's date]).

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