Is ALPL p.Pro261Ser (c.781C>T) pathogenic?

ALPL p.Pro261Ser (c.781C>T) is classified Likely pathogenic in ALPL (ClinVar, Single submitter, 1 submitter; last evaluated 2026-01-19). AlphaMissense: likely benign (0.1719); Very rare (popmax 0.00134%, afr).

How common is ALPL p.Pro261Ser (c.781C>T) in the general population?

ALPL p.Pro261Ser (c.781C>T) is very rare (popmax 0.00134%, afr) (gnomAD).

What do computational predictors say about ALPL p.Pro261Ser (c.781C>T)?

AlphaMissense predicts likely benign (score 0.1719) — an in-silico prediction, not a clinical call.

ALPL p.Pro261Ser

c.781C>T · VCV3713118

Likely pathogenic Single submitter

Classification

Likely pathogenic

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1719 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00134%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.1719	likely benign ⚠ discordant with ClinVar
REVEL	0.615	indeterminate
SaProt	LLR -7.12	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 6	GERP 1.3, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 24 kb · p 6.1e-06 · regional, not allelic
Overall
CADD	24.0	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 0.00134% African / African-American · 1/74,894 alleles

Filtering AF 0.000542% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000428%

Overall 0.000867% 14/1,613,914 alleles · very rare exomes 13/1,461,860 · genomes 1/152,054 · joint denominator

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0016%	62,480
African / African-Americangrpmax	0.00134%	74,894
European (non-Finnish)	0.00102%	98,334

Remaining individuals 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
Protein: p.Pro261Ser
Coding: c.781C>T
MANE Select: NM_000478
Type: single nucleotide variant
Location: chr1:21568236 (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 p.Pro261Gln Uncertain significance ★★ ⚠ same residue
ALPL p.Pro261Thr Uncertain significance ★★ ⚠ same residue
ALPL p.Pro261Leu Conflicting classifications of pathogenicity ★ ⚠ same residue
ALPL p.Pro261= 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

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-pro261ser (accessed [today's date]).

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