Is APP p.Ser198Pro (c.592T>C) pathogenic?

APP p.Ser198Pro (c.592T>C) is classified Conflicting classifications of pathogenicity in APP (ClinVar, Conflicting submitters, 5 submitters; last evaluated 2025-08-10). AlphaMissense: likely benign (0.1029); Ultra-rare (popmax 0.0433%, amr); Associated with Alzheimer disease.

What condition is associated with APP p.Ser198Pro (c.592T>C)?

APP p.Ser198Pro (c.592T>C) is associated with Alzheimer disease (ClinVar).

How common is APP p.Ser198Pro (c.592T>C) in the general population?

APP p.Ser198Pro (c.592T>C) is ultra-rare (popmax 0.0433%, amr) (gnomAD).

What do computational predictors say about APP p.Ser198Pro (c.592T>C)?

AlphaMissense predicts likely benign (score 0.1029) — an in-silico prediction, not a clinical call.

APP p.Ser198Pro

c.592T>C · rs145081708 · VCV339645

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 5 submitters

AlphaMissense

likely benign

0.1029 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0433%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Alzheimer disease

Computational evidence

Protein change
AlphaMissense	0.1029	likely benign
REVEL	0.547	indeterminate
SaProt	LLR -7.03	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7	GERP 0.59, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	22.6	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 0.0433% Admixed American · 26/59,998 alleles

Filtering AF 0.0303% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.026%

Overall 0.0319% 515/1,614,066 alleles · ultra-rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	1.17%	85
Remaining individualsnot grpmax-eligible	0.0976%	1,024
Admixed Americangrpmax	0.0433%	2,308
European (non-Finnish)	0.00669%	14,937
African / African-American	0.00267%	37,465

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: APP
Protein: p.Ser198Pro
Coding: c.592T>C
MANE Select: NM_000484
dbSNP: rs145081708
Type: single nucleotide variant
Location: chr21:26051070 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 198: the 'disordered' region; a functional site (cleavage; by caspases); a modified residue (phosphoserine; by ck2)

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

Disease context

Alzheimer disease — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

APP p.Ala713Thr Likely pathogenic ★★ ⚠ same condition
APP p.Asp694Asn Pathogenic ★★ ⚠ same condition
APP p.Glu693Gln Pathogenic ★★ ⚠ same condition
APP p.Ile716Phe Pathogenic ★★ ⚠ same condition
APP p.Thr714Ala Pathogenic ★★ ⚠ same condition
APP p.Val715Met Pathogenic/Likely pathogenic ★★ ⚠ same condition
APP p.Val717Ile Pathogenic ★★ ⚠ same condition
APP p.Val717Phe Pathogenic ★★ ⚠ 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/app-p-ser198pro (accessed [today's date]).

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