Is ALPL p.Ile55Val (c.163A>G) pathogenic?

ALPL p.Ile55Val (c.163A>G) is classified Uncertain significance in ALPL (ClinVar, Multiple submitters, 2 submitters; last evaluated 2024-09-23). AlphaMissense: likely benign (0.1433); Very rare (popmax 0.00667%, amr).

How common is ALPL p.Ile55Val (c.163A>G) in the general population?

ALPL p.Ile55Val (c.163A>G) is very rare (popmax 0.00667%, amr) (gnomAD).

What do computational predictors say about ALPL p.Ile55Val (c.163A>G)?

AlphaMissense predicts likely benign (score 0.1433) — an in-silico prediction, not a clinical call.

ALPL p.Ile55Val

c.163A>G · rs963835902 · VCV2139316

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1433 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00667%, amr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1433	likely benign
REVEL	0.467	indeterminate
SaProt	LLR -9.37	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 7.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	21.6	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 0.00667% Admixed American · 4/60,004 alleles

Filtering AF 0.00226% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00135%

Overall 0.000496% 8/1,613,984 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00667%	15,001
European (non-Finnish)	0.000339%	294,996

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: ALPL
Protein: p.Ile55Val
Coding: c.163A>G
MANE Select: NM_000478
dbSNP: rs963835902
Type: single nucleotide variant
Location: chr1:21560727 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 55: a β-strand

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

Similar variants

ALPL p.Ile55Phe Uncertain significance ★★ ⚠ same residue
ALPL p.Ile55Asn Likely pathogenic ★ same residue
ALPL p.Ile55del Uncertain significance ★★ same residue
ALPL c.1190-2A>T Pathogenic ★★ same type
ALPL c.182-1G>A Pathogenic/Likely pathogenic ★★ same type
ALPL c.182-2A>G Pathogenic/Likely pathogenic ★★ same type
ALPL c.297+1G>A Pathogenic/Likely pathogenic ★★ same type
ALPL c.298-1G>A 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/alpl-p-ile55val (accessed [today's date]).

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