Is AMOTL2 p.Ser206Phe (c.617C>T) pathogenic?

AMOTL2 p.Ser206Phe (c.617C>T) is classified Uncertain significance in AMOTL2 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-07-31). AlphaMissense: likely benign (0.0965); Ultra-rare (popmax 0.0109%, afr).

How common is AMOTL2 p.Ser206Phe (c.617C>T) in the general population?

AMOTL2 p.Ser206Phe (c.617C>T) is ultra-rare (popmax 0.0109%, afr) (gnomAD).

What do computational predictors say about AMOTL2 p.Ser206Phe (c.617C>T)?

AlphaMissense predicts likely benign (score 0.0965) — an in-silico prediction, not a clinical call.

AMOTL2 p.Ser206Phe

c.617C>T · VCV3536438

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0965 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0109%, afr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0965	likely benign
REVEL	0.022	moderately benign-leaning
SaProt	LLR -7.75	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 2.4	GERP 0.64, phastCons 0.62
Regional constraint	o/e 0.95	unconstrained · MANE · 14 kb · p 0.14 · regional, not allelic
Overall
CADD	20.4	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 0.0109% African / African-American · 8/73,620 alleles

Filtering AF 0.00536% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00386%

Overall 0.000762% 12/1,574,284 alleles · ultra-rare

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.0109%	9,203
South Asian	0.00234%	42,797
Remaining individualsnot grpmax-eligible	0.00165%	60,494
European (non-Finnish)	8.62e-05%	1,159,539

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: AMOTL2
Protein: p.Ser206Phe
Coding: c.617C>T
MANE Select: NM_016201
Type: single nucleotide variant
Location: chr3:134370817 (GRCh38)
Gene constraint: LOEUF 0.574 · pLI 0.06 (gnomAD)
Structure: AlphaFold pLDDT 67.35
Residue 206: the 'disordered' region; the 'required for interaction with cdh5' region

Full AMOTL2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

AMOTL2 p.Arg369His Uncertain significance ★★ ⚠ same type
AMOTL2 p.Arg173Gln Benign/Likely benign ★★ same type
AMOTL2 p.Ala118Gly Uncertain significance ★ ⚠ same type
AMOTL2 p.Ala122Thr Uncertain significance ★ ⚠ same type
AMOTL2 p.Ala174Val Uncertain significance ★ ⚠ same type
AMOTL2 p.Ala242Thr Uncertain significance ★ ⚠ same type
AMOTL2 p.Ala304Thr Uncertain significance ★ ⚠ same type
AMOTL2 p.Ala339Val 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/amotl2-p-ser206phe (accessed [today's date]).

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