Is APLP1 p.Arg229Trp (c.685C>T) pathogenic?

APLP1 p.Arg229Trp (c.685C>T) is classified Uncertain significance in APLP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-10-02). AlphaMissense: likely benign (0.0927); Ultra-rare (popmax 0.0209%, sas).

How common is APLP1 p.Arg229Trp (c.685C>T) in the general population?

APLP1 p.Arg229Trp (c.685C>T) is ultra-rare (popmax 0.0209%, sas) (gnomAD).

What do computational predictors say about APLP1 p.Arg229Trp (c.685C>T)?

AlphaMissense predicts likely benign (score 0.0927) — an in-silico prediction, not a clinical call.

APLP1 p.Arg229Trp

c.685C>T · rs375123845 · VCV3127856

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0927 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0209%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.0927	likely benign
REVEL	0.302	indeterminate
SaProt	LLR -7.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · C>A here scores Δ0.62 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.85	GERP -0.55, phastCons 0.23
Regional constraint	o/e 1.01	unconstrained · MANE · 3,350 bp · p 0.81 · regional, not allelic
Overall
CADD	22.9	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 0.0209% South Asian · 19/91,064 alleles

Filtering AF 0.0136% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0114%

Overall 0.00762% 123/1,613,844 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0209%	4,793
European (non-Finnish)	0.00831%	12,040
Remaining individualsnot grpmax-eligible	0.0048%	20,825
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,570
Finnishnot grpmax-eligible	0.00156%	64,028
African / African-American	0.00133%	74,922

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: APLP1
Protein: p.Arg229Trp
Coding: c.685C>T
MANE Select: NM_001024807
dbSNP: rs375123845
Type: single nucleotide variant
Location: chr19:35871871 (GRCh38)
Gene constraint: LOEUF 0.713 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 69.36 · 6 PDB
Residue 229: the 'disordered' region

Full APLP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

APLP1 p.Arg229Gln Uncertain significance ★ ⚠ same residue
APLP1 p.Ala149Asp Uncertain significance ★ ⚠ same type
APLP1 p.Ala222Pro Uncertain significance ★ ⚠ same type
APLP1 p.Ala263Thr Uncertain significance ★ ⚠ same type
APLP1 p.Ala382Thr Uncertain significance ★ ⚠ same type
APLP1 p.Ala391Val Uncertain significance ★ ⚠ same type
APLP1 p.Ala412Thr Uncertain significance ★ ⚠ same type
APLP1 p.Ala47Glu 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/aplp1-p-arg229trp (accessed [today's date]).

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