Is ALPI p.Ser174= (c.522G>A) pathogenic?

ALPI p.Ser174= (c.522G>A) is classified Likely benign in ALPI (ClinVar, Single submitter, 2 submitters; last evaluated 2024-11-23). Rare (popmax 0.116%, mid).

How common is ALPI p.Ser174= (c.522G>A) in the general population?

ALPI p.Ser174= (c.522G>A) is rare (popmax 0.116%, mid) (gnomAD).

ALPI p.Ser174=

c.522G>A · rs144872496 · VCV3040610

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Rare

rare (popmax 0.116%, mid)

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -13	GERP -3.7
Overall
CADD	0.482	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.116% Middle Eastern · 7/6,048 alleles

Filtering AF 0.0543% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0385%

Overall 0.0164% 264/1,613,438 alleles · rare

Ancestry group	Frequency	1 in
Ashkenazi Jewishnot grpmax-eligible	0.27%	370
Middle Easterngrpmax	0.116%	864
Remaining individualsnot grpmax-eligible	0.0512%	1,953
European (non-Finnish)	0.0113%	8,872
South Asian	0.00878%	11,384
African / African-American	0.004%	25,017
East Asian	0.00223%	44,868

Ashkenazi Jewish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ALPI
Protein: p.Ser174=
Coding: c.522G>A
MANE Select: NM_001631
dbSNP: rs144872496
Type: single nucleotide variant
Location: chr2:232457196 (GRCh38)
Gene constraint: LOEUF 1.163 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.46
Residue 174: a disulfide bond; a binding site

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

Similar variants

ALPI p.Ser174Leu Uncertain significance ★ ⚠ same residue
ALPI p.Ala97Thr Uncertain significance ★★ ⚠ same type
ALPI p.Arg299Ter Uncertain significance ★★ same type
ALPI p.Gln171Arg Uncertain significance ★★ ⚠ same type
ALPI p.Glu449Asp Uncertain significance ★★ ⚠ same type
ALPI p.Leu9Pro Uncertain significance ★★ ⚠ same type
ALPI p.Pro28Leu Uncertain significance ★★ ⚠ same type
ALPI p.Arg92Cys Likely benign ★★ ⚠ 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/alpi-p-ser174 (accessed [today's date]).

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