Is ADD2 p.Ser11Leu (c.32C>T) pathogenic?

ADD2 p.Ser11Leu (c.32C>T) is classified Uncertain significance in ADD2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-06-17). AlphaMissense: likely benign (0.0729); Very rare (popmax 0.00534%, nfe).

How common is ADD2 p.Ser11Leu (c.32C>T) in the general population?

ADD2 p.Ser11Leu (c.32C>T) is very rare (popmax 0.00534%, nfe) (gnomAD).

What do computational predictors say about ADD2 p.Ser11Leu (c.32C>T)?

AlphaMissense predicts likely benign (score 0.0729) — an in-silico prediction, not a clinical call.

ADD2 p.Ser11Leu

c.32C>T · VCV3269948

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0729 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00534%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0729	likely benign
REVEL	0.03	moderately benign-leaning
SaProt	LLR -7.13	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 12	GERP 1.9, phastCons 1
Regional constraint	o/e 0.91	unconstrained · MANE · 10 kb · p 0.22 · regional, not allelic
Overall
CADD	23.6	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 0.00534% European (non-Finnish) · 63/1,178,760 alleles

Filtering AF 0.00427% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00388%

Overall 0.00434% 70/1,611,214 alleles · very rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00534%	18,710
East Asian	0.00446%	22,421
Admixed American	0.00334%	29,953
Remaining individualsnot grpmax-eligible	0.0016%	62,418
African / African-American	0.00133%	74,938
South Asian	0.0011%	90,944

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: ADD2
Protein: p.Ser11Leu
Coding: c.32C>T
MANE Select: NM_001617
Type: single nucleotide variant
Location: chr2:70706377 (GRCh38)
Gene constraint: LOEUF 0.388 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.51
Residue 11: the 'disordered' region; a modified residue (phosphoserine)

Full ADD2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADD2 p.Asp28Asn Benign ★★ ⚠ same type
ADD2 p.Glu335Asp Benign ★★ same type
ADD2 p.Gly17Glu Benign ★★ same type
ADD2 p.Ala150Val Uncertain significance ★ ⚠ same type
ADD2 p.Ala232Gly Uncertain significance ★ ⚠ same type
ADD2 p.Ala312Thr Uncertain significance ★ ⚠ same type
ADD2 p.Ala418Pro Uncertain significance ★ ⚠ same type
ADD2 p.Ala606Val 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/add2-p-ser11leu (accessed [today's date]).

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