Is ADAM11 p.Ser718Phe (c.2153C>T) pathogenic?

ADAM11 p.Ser718Phe (c.2153C>T) is classified Uncertain significance in ADAM11 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-15). AlphaMissense: likely benign (0.0976); Very rare (popmax 0.00133%, afr).

How common is ADAM11 p.Ser718Phe (c.2153C>T) in the general population?

ADAM11 p.Ser718Phe (c.2153C>T) is very rare (popmax 0.00133%, afr) (gnomAD).

What do computational predictors say about ADAM11 p.Ser718Phe (c.2153C>T)?

AlphaMissense predicts likely benign (score 0.0976) — an in-silico prediction, not a clinical call.

ADAM11 p.Ser718Phe

c.2153C>T · rs765259219 · VCV2510262

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0976 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00133%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0976	likely benign
REVEL	0.095	moderately benign-leaning
SaProt	LLR -8.59	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 7.5	GERP 2, phastCons 0.96
Regional constraint	o/e 0.72	unconstrained · MANE · 4,510 bp · p 3.3e-10 · regional, not allelic
Overall
CADD	23.9	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 0.00133% African / African-American · 1/74,910 alleles

Filtering AF 0.000763% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000605%

Overall 0.00105% 17/1,613,660 alleles · very rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00133%	74,910
European (non-Finnish)	0.00127%	78,658
South Asian	0.0011%	90,972

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: ADAM11
Protein: p.Ser718Phe
Coding: c.2153C>T
MANE Select: NM_002390
dbSNP: rs765259219
Type: single nucleotide variant
Location: chr17:44778034 (GRCh38)
Gene constraint: LOEUF 0.584 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 80.04
Residue 718: the 'required for localization to cerebellar cortex basket cell terminals. also required for localization of kcna1, kcna2, dlg4 and adam22 to cerebellar cortex basket cell terminal perisomatic axons and pinceaux' region

Full ADAM11 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ADAM11 p.Thr717Met Uncertain significance ★★ ⚠ same type
ADAM11 p.Ala147Thr Uncertain significance ★ ⚠ same type
ADAM11 p.Ala148Thr Uncertain significance ★ ⚠ same type
ADAM11 p.Ala214Ser Uncertain significance ★ ⚠ same type
ADAM11 p.Ala214Thr Uncertain significance ★ ⚠ same type
ADAM11 p.Ala326Thr Uncertain significance ★ ⚠ same type
ADAM11 p.Ala342Val Uncertain significance ★ ⚠ same type
ADAM11 p.Ala561Val 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/adam11-p-ser718phe (accessed [today's date]).

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