Is ABCA7 p.Ala2045Ser (c.6133G>T) pathogenic?

ABCA7 p.Ala2045Ser (c.6133G>T) is classified Benign in ABCA7 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-08-22). AlphaMissense: likely benign (0.1402); Common (popmax 80.1%, amr) — too common for a highly-penetrant pathogenic allele.

What do computational predictors say about ABCA7 p.Ala2045Ser (c.6133G>T)?

AlphaMissense predicts likely benign (score 0.1402) — an in-silico prediction, not a clinical call.

ABCA7 p.Ala2045Ser

Q: How common is ABCA7 p.Ala2045Ser (c.6133G>T) in the general population?

ABCA7 p.Ala2045Ser (c.6133G>T) is common (popmax 80.1%, amr) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.6133G>T · rs4147934 · VCV1269149

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1402 · ACMG-weighted

gnomAD v4.1

Common

common (popmax 80.1%, amr) — too common for a highly-penetrant pathogenic allele

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1402	likely benign
REVEL	0.097	moderately benign-leaning
SaProt	LLR -11.10	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.8	GERP -1.6, phastCons 0.85
Regional constraint	o/e 1.14	unconstrained · MANE · 24 kb · p 5.6e-14 · regional, not allelic
Overall
CADD	12.67	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 80.1% Admixed American · 41,729/52,124 alleles

Filtering AF 79.4% ClinGen BA1/BS1 input FAF95, joint · FAF99 79.1%

Overall 71.7% 1,114,896/1,555,404 alleles · common

Ancestry group	Frequency	1 in
Admixed Americangrpmax	80.1%	1
Finnishnot grpmax-eligible	75.4%	1
Middle Eastern	74.7%	1
European (non-Finnish)	73.5%	1
Ashkenazi Jewishnot grpmax-eligible	71.6%	1
Remaining individualsnot grpmax-eligible	69.7%	1
South Asian	63.2%	2
African / African-American	61.9%	2
Amishnot grpmax-eligible	49.7%	2
East Asian	44.1%	2

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: ABCA7
Protein: p.Ala2045Ser
Coding: c.6133G>T
MANE Select: NM_019112
dbSNP: rs4147934
Type: single nucleotide variant
Location: chr19:1065019 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.77 · 6 PDB
Residue 2045: a UniProt-annotated variant site (in)

Full ABCA7 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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ABCA7 p.Arg652Cys Uncertain significance ★★ ⚠ same type
ABCA7 p.Arg880Trp Uncertain significance ★★ ⚠ same type
ABCA7 p.Asp1452Asn Uncertain significance ★★ ⚠ same type
ABCA7 p.Asp2085Asn Uncertain significance ★★ same type
ABCA7 p.Gln925Ter 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/abca7-p-ala2045ser (accessed [today's date]).

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