Is ALPL c.792+268C>T pathogenic?

ALPL c.792+268C>T is classified Benign in ALPL (ClinVar, Single submitter, 1 submitter; last evaluated 2018-08-09). Common (popmax 23.8%, nfe) — too common for a highly-penetrant pathogenic allele.

ALPL c.792+268C>T

Q: How common is ALPL c.792+268C>T in the general population?

ALPL c.792+268C>T is common (popmax 23.8%, nfe) — too common for a highly-penetrant pathogenic allele (gnomAD).

rs1256331 · VCV1264498

Benign Single submitter

Classification

Benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

gnomAD v4.1

Common

common (popmax 23.8%, nfe) — 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
Splice region	donor +268	deep intronic (+268 nt into the intron)
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -1.8	GERP -2.1
Non-coding constraint	Z 3.14	1 kb window · o/e 0.78 · regional · uncalibrated
Overall
CADD	6.175	PHRED · no single calibrated threshold — expert panels disagree

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 23.8% European (non-Finnish) · 16,196/67,952 alleles

Filtering AF 23.5% ClinGen BA1/BS1 input FAF95, joint · FAF99 23.4%

Overall 15.8% 24,078/152,058 alleles · common

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	29.5%	3
European (non-Finnish)grpmax	23.8%	4
Ashkenazi Jewishnot grpmax-eligible	21.5%	5
Finnishnot grpmax-eligible	19.1%	5
Middle Eastern	17%	6
Remaining individualsnot grpmax-eligible	15.4%	7
Admixed American	14.9%	7
South Asian	7.95%	13
African / African-American	4.38%	23
East Asian	0.0195%	5,136

Amish 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: ALPL
Coding: c.792+268C>T
MANE Select: NM_000478
dbSNP: rs1256331
Type: single nucleotide variant
Location: chr1:21568515 (GRCh38)
Gene constraint: LOEUF 0.987 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 93.74 · 5 PDB

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

Similar variants

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
ALPL c.648+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-c-792-plus-268c-t (accessed [today's date]).

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