Is APPL1 p.Ser673Cys (c.2018C>G) pathogenic?

APPL1 p.Ser673Cys (c.2018C>G) is classified Conflicting classifications of pathogenicity in APPL1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-01-02). AlphaMissense: ambiguous (0.3547); Rare (popmax 0.181%, mid).

How common is APPL1 p.Ser673Cys (c.2018C>G) in the general population?

APPL1 p.Ser673Cys (c.2018C>G) is rare (popmax 0.181%, mid) (gnomAD).

What do computational predictors say about APPL1 p.Ser673Cys (c.2018C>G)?

AlphaMissense predicts ambiguous (score 0.3547) — an in-silico prediction, not a clinical call.

APPL1 p.Ser673Cys

c.2018C>G · rs138485817 · VCV1336471

Conflicting classifications of pathogenicity Conflicting submitters

Classification

Conflicting classifications of pathogenicity

ClinVar

Review

Conflicting submitters ★☆☆☆

ClinVar · 4 submitters

AlphaMissense

ambiguous

0.3547 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.181%, mid)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3547	ambiguous
REVEL	0.19	benign-leaning
SaProt	LLR -9.23	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2, phastCons 1
Regional constraint	o/e 0.90	unconstrained · MANE · 42 kb · p 0.0023 · regional, not allelic
Overall
CADD	25.6	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 0.181% Middle Eastern · 11/6,062 alleles

Filtering AF 0.108% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.106%

Overall 0.0905% 1,461/1,613,982 alleles · rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.181%	551
European (non-Finnish)	0.113%	882
Remaining individualsnot grpmax-eligible	0.0816%	1,225
Admixed American	0.0383%	2,609
South Asian	0.022%	4,552
African / African-American	0.0213%	4,690
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,596
Finnishnot grpmax-eligible	0.00156%	64,016

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: APPL1
Protein: p.Ser673Cys
Coding: c.2018C>G
MANE Select: NM_012096
dbSNP: rs138485817
Type: single nucleotide variant
Location: chr3:57269575 (GRCh38)
Gene constraint: LOEUF 0.524 · pLI 0.88 (gnomAD)
Structure: AlphaFold pLDDT 81.44 · 8 PDB
Residue 673: the 'disordered' region

Full APPL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APPL1 c.1658+6T>G Uncertain significance ★★ same type
APPL1 p.Arg275Gln Uncertain significance ★★ ⚠ same type
APPL1 p.Arg407Ser Uncertain significance ★★ ⚠ same type
APPL1 p.Arg412Trp Uncertain significance ★★ ⚠ same type
APPL1 p.Arg478Cys Uncertain significance ★★ ⚠ same type
APPL1 p.Arg526His Uncertain significance ★★ ⚠ same type
APPL1 p.Arg633His Uncertain significance ★★ ⚠ same type
APPL1 p.Arg72Cys 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/appl1-p-ser673cys (accessed [today's date]).

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