Is ABCA7 p.Pro1692Ser (c.5074C>T) pathogenic?

ABCA7 p.Pro1692Ser (c.5074C>T) is classified Uncertain significance in ABCA7 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-14). AlphaMissense: likely pathogenic (0.9378); Very rare (popmax 0.00267%, afr).

How common is ABCA7 p.Pro1692Ser (c.5074C>T) in the general population?

ABCA7 p.Pro1692Ser (c.5074C>T) is very rare (popmax 0.00267%, afr) (gnomAD).

What do computational predictors say about ABCA7 p.Pro1692Ser (c.5074C>T)?

AlphaMissense predicts likely pathogenic (score 0.9378) — an in-silico prediction, not a clinical call.

ABCA7 p.Pro1692Ser

c.5074C>T · rs2042415978 · VCV2267111

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9378 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00267%, afr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9378	likely pathogenic · top 2% in ABCA7
REVEL	0.865	moderately pathogenic-leaning
SaProt	LLR -8.82	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.7	GERP 1.9, phastCons 1
Regional constraint	o/e 1.14	unconstrained · MANE · 24 kb · p 5.6e-14 · regional, not allelic
Overall
CADD	25.5	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 0.00267% African / African-American · 2/74,812 alleles

Filtering AF 0.000444% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000166%

Overall 0.000137% 2/1,461,694 alleles · very rare

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.Pro1692Ser
Coding: c.5074C>T
MANE Select: NM_019112
dbSNP: rs2042415978
Type: single nucleotide variant
Location: chr19:1058194 (GRCh38)
Gene constraint: LOEUF 1.368 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.77 · 6 PDB
Residue 1692: a turn

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

Similar variants

ABCA7 c.2684+5G>A Uncertain significance ★★ same type
ABCA7 c.3578-2A>G Uncertain significance ★★ same type
ABCA7 p.Arg1026Cys Uncertain significance ★★ ⚠ same type
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-pro1692ser (accessed [today's date]).

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