Is ALPL p.Ala352Val (c.1055C>T) pathogenic?

ALPL p.Ala352Val (c.1055C>T) is classified Uncertain significance in ALPL (ClinVar, Single submitter, 1 submitter; last evaluated 2022-09-18). AlphaMissense: likely benign (0.1636); Ultra-rare (popmax 0.0164%, mid).

How common is ALPL p.Ala352Val (c.1055C>T) in the general population?

ALPL p.Ala352Val (c.1055C>T) is ultra-rare (popmax 0.0164%, mid) (gnomAD).

What do computational predictors say about ALPL p.Ala352Val (c.1055C>T)?

AlphaMissense predicts likely benign (score 0.1636) — an in-silico prediction, not a clinical call.

ALPL p.Ala352Val

c.1055C>T · rs1212356217 · VCV2148087

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1636 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0164%, mid)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1636	likely benign
REVEL	0.446	indeterminate
SaProt	LLR -7.28	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 0.46	GERP 0.48, phastCons 0.037
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	21.1	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 0.0164% Middle Eastern · 1/6,084 alleles

Filtering AF 0.000553% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000207%

Overall 0.000496% 8/1,614,096 alleles · ultra-rare

Ancestry group	Frequency	1 in
Middle Easterngrpmax	0.0164%	6,084
Admixed American	0.00333%	30,005
African / African-American	0.00133%	74,924
European (non-Finnish)	0.000339%	295,013

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.Ala352Val
Coding: c.1055C>T
MANE Select: NM_000478
dbSNP: rs1212356217
Type: single nucleotide variant
Location: chr1:21575790 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 352: an α-helix

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

Similar variants

ALPL p.Ala352= Likely benign ★★ 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
ALPL c.472+1G>A Pathogenic ★★ same type
ALPL c.62-1G>C Pathogenic/Likely 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-ala352val (accessed [today's date]).

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