Is ADAP2 p.Leu139Pro (c.416T>C) pathogenic?

ADAP2 p.Leu139Pro (c.416T>C) is classified Uncertain significance in ADAP2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-06). AlphaMissense: likely pathogenic (0.9836); Very rare (popmax 0.00585%, nfe).

How common is ADAP2 p.Leu139Pro (c.416T>C) in the general population?

ADAP2 p.Leu139Pro (c.416T>C) is very rare (popmax 0.00585%, nfe) (gnomAD).

What do computational predictors say about ADAP2 p.Leu139Pro (c.416T>C)?

AlphaMissense predicts likely pathogenic (score 0.9836) — an in-silico prediction, not a clinical call.

ADAP2 p.Leu139Pro

c.416T>C · VCV3493269

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9836 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00585%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.9836	likely pathogenic · top 3% in ADAP2
REVEL	0.501	indeterminate
SaProt	LLR -15.15	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.6, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 36 kb · p 0.019 · regional, not allelic
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 0.00585% European (non-Finnish) · 69/1,179,974 alleles

Filtering AF 0.0047% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00431%

Overall 0.0044% 71/1,613,952 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00585%	17,101
Admixed American	0.00167%	59,984
Remaining individualsnot grpmax-eligible	0.0016%	62,472

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: ADAP2
Protein: p.Leu139Pro
Coding: c.416T>C
MANE Select: NM_018404
Type: single nucleotide variant
Location: chr17:30934203 (GRCh38)
Gene constraint: LOEUF 1.031 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 92.49
Residue 139: the ph 1 domain

Full ADAP2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAP2 p.Ala279Thr Uncertain significance ★ ⚠ same type
ADAP2 p.Ala36Ser Uncertain significance ★ ⚠ same type
ADAP2 p.Arg16Gly Uncertain significance ★ ⚠ same type
ADAP2 p.Arg209Lys Uncertain significance ★ ⚠ same type
ADAP2 p.Arg229His Uncertain significance ★ ⚠ same type
ADAP2 p.Arg254Lys Uncertain significance ★ ⚠ same type
ADAP2 p.Arg285Gln Uncertain significance ★ ⚠ same type
ADAP2 p.Arg322Gln 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/adap2-p-leu139pro (accessed [today's date]).

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