Is APP p.His110= (c.330C>T) pathogenic?

APP p.His110= (c.330C>T) is classified Likely benign in APP (ClinVar, Single submitter, 1 submitter; last evaluated 2024-10-21). Very rare (popmax 0.0011%, sas).

How common is APP p.His110= (c.330C>T) in the general population?

APP p.His110= (c.330C>T) is very rare (popmax 0.0011%, sas) (gnomAD).

APP p.His110=

c.330C>T · VCV4946003

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
REVEL	0.128	moderately benign-leaning
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.5	GERP 1.7, phastCons 1
Overall
CADD	9.751	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.0011% South Asian · 1/91,092 alleles

Overall 0.000124% 2/1,614,066 alleles · very rare exomes 1/1,461,864 · genomes 1/152,202 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,488
South Asiangrpmax	0.0011%	91,092

Remaining individuals 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.His110=
Coding: c.330C>T
MANE Select: NM_000484
Type: single nucleotide variant
Location: chr21:26089968 (GRCh38)
Gene constraint: LOEUF 0.41 · pLI 1.00 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 68.11 · 263 PDB
Residue 110: the e1 domain; a β-strand; the 'gfld subdomain' region; a binding site

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

Similar variants

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
APP p.Val717Phe 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-his110 (accessed [today's date]).

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