Is ADAP1 p.Pro126Leu (c.377C>T) pathogenic?

ADAP1 p.Pro126Leu (c.377C>T) is classified Uncertain significance in ADAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-14). AlphaMissense: likely benign (0.1592); Very rare (popmax 0.000339%, nfe).

How common is ADAP1 p.Pro126Leu (c.377C>T) in the general population?

ADAP1 p.Pro126Leu (c.377C>T) is very rare (popmax 0.000339%, nfe) (gnomAD).

What do computational predictors say about ADAP1 p.Pro126Leu (c.377C>T)?

AlphaMissense predicts likely benign (score 0.1592) — an in-silico prediction, not a clinical call.

ADAP1 p.Pro126Leu

c.377C>T · rs769371283 · VCV2487385

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1592 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000339%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1592	likely benign
REVEL	0.078	moderately benign-leaning
SaProt	LLR -6.63	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 11	GERP 1.9, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 56 kb · p 0.32 · regional, not allelic
Overall
CADD	24.5	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.000339% European (non-Finnish) · 4/1,179,362 alleles

Filtering AF 7.9e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 5.4e-05%

Overall 0.000275% 4/1,454,672 alleles · very rare

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: ADAP1
Protein: p.Pro126Leu
Coding: c.377C>T
MANE Select: NM_006869
dbSNP: rs769371283
Type: single nucleotide variant
Location: chr7:919979 (GRCh38)
Gene constraint: LOEUF 0.949 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 95.96 · 4 PDB
Residue 126: the arf-gap domain; an α-helix

Full ADAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAP1 p.Ala168Val Uncertain significance ★ same type
ADAP1 p.Ala182Thr Uncertain significance ★ ⚠ same type
ADAP1 p.Ala243Thr Uncertain significance ★ ⚠ same type
ADAP1 p.Ala26Val Uncertain significance ★ ⚠ same type
ADAP1 p.Ala293Val Uncertain significance ★ ⚠ same type
ADAP1 p.Ala349Val Uncertain significance ★ ⚠ same type
ADAP1 p.Ala81Glu Uncertain significance ★ ⚠ same type
ADAP1 p.Ala81Val 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/adap1-p-pro126leu (accessed [today's date]).

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