Is ALPI p.Ser111= (c.333C>T) pathogenic?

ALPI p.Ser111= (c.333C>T) is classified Benign in ALPI (ClinVar, Single submitter, 2 submitters; last evaluated 2022-09-06). Common (popmax 12.8%, mid) — too common for a highly-penetrant pathogenic allele.

ALPI p.Ser111=

Q: How common is ALPI p.Ser111= (c.333C>T) in the general population?

ALPI p.Ser111= (c.333C>T) is common (popmax 12.8%, mid) — too common for a highly-penetrant pathogenic allele (gnomAD).

c.333C>T · rs61732032 · VCV3055586

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 2 submitters

gnomAD v4.1

Common

common (popmax 12.8%, mid) — too common for a highly-penetrant pathogenic allele

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 -20	GERP -3.7
Overall
CADD	7.389	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 12.8% Middle Eastern · 777/6,062 alleles

Filtering AF 12.1% ClinGen BA1/BS1 input FAF95, joint · FAF99 11.8%

Overall 8.74% 140,982/1,613,426 alleles · common exomes 126,664/1,461,214 · genomes 14,318/152,212 · joint denominator

Ancestry group	Frequency	1 in
Middle Easterngrpmax	12.8%	8
African / African-American	11.3%	9
South Asian	10.4%	10
Finnishnot grpmax-eligible	9.77%	10
Remaining individualsnot grpmax-eligible	9.28%	11
Ashkenazi Jewishnot grpmax-eligible	8.96%	11
European (non-Finnish)	8.45%	12
East Asian	8.21%	12
Amishnot grpmax-eligible	7.8%	13
Admixed American	7.01%	14

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.Ser111=
Coding: c.333C>T
MANE Select: NM_001631
dbSNP: rs61732032
Type: single nucleotide variant
Location: chr2:232456931 (GRCh38)
Gene constraint: LOEUF 1.163 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.46
Residue 111: an active site; a binding site

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

Similar variants

ALPI p.Ser111Thr 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-ser111 (accessed [today's date]).

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