Is APP p.Asn164Ser (c.491A>G) pathogenic?

APP p.Asn164Ser (c.491A>G) is classified Uncertain significance in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2017-11-01). AlphaMissense: likely benign (0.0672); Very rare (popmax 0.000169%, nfe).

How common is APP p.Asn164Ser (c.491A>G) in the general population?

APP p.Asn164Ser (c.491A>G) is very rare (popmax 0.000169%, nfe) (gnomAD).

What do computational predictors say about APP p.Asn164Ser (c.491A>G)?

AlphaMissense predicts likely benign (score 0.0672) — an in-silico prediction, not a clinical call.

APP p.Asn164Ser

c.491A>G · rs1231783932 · VCV546904

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0672 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000169%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0672	likely benign
REVEL	0.346	indeterminate
SaProt	LLR -4.27	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 5.1	GERP -3.7, phastCons 1
Regional constraint	o/e 0.84	unconstrained · MANE · 289 kb · p 2e-07 · regional, not allelic
Overall
CADD	23.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000169% European (non-Finnish) · 2/1,179,960 alleles

Filtering AF 2.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.1e-05%

Overall 0.000137% 2/1,461,714 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: APP
Protein: p.Asn164Ser
Coding: c.491A>G
MANE Select: NM_000484
dbSNP: rs1231783932
Type: single nucleotide variant
Location: chr21:26051171 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 164: the e1 domain; a β-strand; the 'cubd subdomain' region

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

Similar variants

APP p.Asn164Ile Uncertain significance ★ ⚠ same residue
APP p.Ala713Thr Likely pathogenic ★★ ⚠ same type
APP p.Asp694Asn Pathogenic ★★ ⚠ same type
APP p.Glu693Gln Pathogenic ★★ ⚠ same type
APP p.Ile716Phe Pathogenic ★★ ⚠ same type
APP p.Thr714Ala Pathogenic ★★ ⚠ same type
APP p.Val715Met Pathogenic/Likely pathogenic ★★ ⚠ same type
APP p.Val717Ile Pathogenic ★★ ⚠ 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/app-p-asn164ser (accessed [today's date]).

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