Is ALPL p.Ile204Val (c.610A>G) pathogenic?

ALPL p.Ile204Val (c.610A>G) is classified Uncertain significance in ALPL (ClinVar, Multiple submitters, 4 submitters; last evaluated 2025-01-29). AlphaMissense: likely benign (0.2827); Very rare (popmax 0.00801%, afr); Associated with Inborn genetic diseases.

What condition is associated with ALPL p.Ile204Val (c.610A>G)?

ALPL p.Ile204Val (c.610A>G) is associated with Inborn genetic diseases, adult hypophosphatasia, childhood hypophosphatasia (ClinVar).

How common is ALPL p.Ile204Val (c.610A>G) in the general population?

ALPL p.Ile204Val (c.610A>G) is very rare (popmax 0.00801%, afr) (gnomAD).

What do computational predictors say about ALPL p.Ile204Val (c.610A>G)?

AlphaMissense predicts likely benign (score 0.2827) — an in-silico prediction, not a clinical call.

ALPL p.Ile204Val

c.610A>G · rs374558572 · VCV591818

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 4 submitters

AlphaMissense

likely benign

0.2827 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00801%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.2827	likely benign
REVEL	0.783	moderately pathogenic-leaning
SaProt	LLR -9.02	tolerated
⇒ REVEL calls this damaging; AlphaMissense and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 8	GERP 1.9, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	24.4	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 0.00801% African / African-American · 6/74,918 alleles

Filtering AF 0.00347% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00229%

Overall 0.000496% 8/1,613,924 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00801%	12,486
European (non-Finnish)	0.000169%	590,009

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.Ile204Val
Coding: c.610A>G
MANE Select: NM_000478
dbSNP: rs374558572
Type: single nucleotide variant
Location: chr1:21564178 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB
Residue 204: an α-helix

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

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: adult hypophosphatasia childhood hypophosphatasia infantile hypophosphatasia

Similar variants

ALPL p.Ile204Met Uncertain significance ★ ⚠ same residue
ALPL p.Ile204Phe Uncertain significance ★★ ⚠ same residue
ALPL p.Ile204= Conflicting classifications of pathogenicity ★ same residue
ALPL c.1190-2A>T Pathogenic ★★ same condition
ALPL c.298-1G>A Pathogenic ★★ same condition
ALPL c.62-1G>C Pathogenic/Likely pathogenic ★★ same condition
ALPL c.648+1G>A Pathogenic ★★ same condition
ALPL c.648+1G>T Pathogenic ★★ same condition

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-ile204val (accessed [today's date]).

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