Is ASAP2 p.Pro868Leu (c.2603C>T) pathogenic?

ASAP2 p.Pro868Leu (c.2603C>T) is classified Benign in ASAP2 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2018-08-01). AlphaMissense: likely benign (0.0678); Low-frequency (popmax 1.21%, sas).

How common is ASAP2 p.Pro868Leu (c.2603C>T) in the general population?

ASAP2 p.Pro868Leu (c.2603C>T) is low-frequency (popmax 1.21%, sas) (gnomAD).

What do computational predictors say about ASAP2 p.Pro868Leu (c.2603C>T)?

AlphaMissense predicts likely benign (score 0.0678) — an in-silico prediction, not a clinical call.

ASAP2 p.Pro868Leu

c.2603C>T · rs145511943 · VCV712925

Benign Multiple submitters

Classification

Benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.0678 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 1.21%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0678	likely benign
REVEL	0.051	moderately benign-leaning
SaProt	LLR -6.99	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4	GERP -3.7, phastCons 0.32
Regional constraint	o/e 0.93	unconstrained · MANE · 44 kb · p 0.076 · regional, not allelic
Overall
CADD	9.347	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 1.21% South Asian · 1,082/89,152 alleles

Filtering AF 1.15% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.13%

Overall 0.467% 7,467/1,599,870 alleles · low-frequency

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	1.86%	54
South Asiangrpmax	1.21%	82
Remaining individualsnot grpmax-eligible	0.501%	200
European (non-Finnish)	0.48%	208
Middle Eastern	0.432%	231
Ashkenazi Jewishnot grpmax-eligible	0.297%	337
Admixed American	0.209%	478
Finnishnot grpmax-eligible	0.191%	523
African / African-American	0.087%	1,149
East Asian	0.00227%	44,124

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: ASAP2
Protein: p.Pro868Leu
Coding: c.2603C>T
MANE Select: NM_003887
dbSNP: rs145511943
Type: single nucleotide variant
Location: chr2:9393566 (GRCh38)
Gene constraint: LOEUF 0.465 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 75.71
Residue 868: the 'disordered' region

Full ASAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ASAP2 p.Ala592= Benign ★★ same type
ASAP2 p.Asp434= Benign ★★ same type
ASAP2 p.Asp45= Benign ★★ same type
ASAP2 c.687-1G>T Uncertain significance ★ same type
ASAP2 p.Ala1005Thr Uncertain significance ★ ⚠ same type
ASAP2 p.Ala276Thr Uncertain significance ★ ⚠ same type
ASAP2 p.Ala31Val Uncertain significance ★ ⚠ same type
ASAP2 p.Ala441Val Uncertain significance ★ ⚠ 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/asap2-p-pro868leu (accessed [today's date]).

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