Is AMER3 p.Arg746Ter (c.2236C>T) pathogenic?

AMER3 p.Arg746Ter (c.2236C>T) is classified Likely pathogenic in AMER3 (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-07-01). Very rare (popmax 0.00306%, nfe); Associated with esophageal atresia/tracheoesophageal fistula.

What condition is associated with AMER3 p.Arg746Ter (c.2236C>T)?

AMER3 p.Arg746Ter (c.2236C>T) is associated with esophageal atresia/tracheoesophageal fistula (ClinVar).

How common is AMER3 p.Arg746Ter (c.2236C>T) in the general population?

AMER3 p.Arg746Ter (c.2236C>T) is very rare (popmax 0.00306%, nfe) (gnomAD).

AMER3 p.Arg746Ter

c.2236C>T · rs768719549 · VCV916554

Likely pathogenic No assertion criteria

Classification

Likely pathogenic

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

Consequence

nonsense (stop-gain)

predicted LoF

gnomAD v4.1

Rare

very rare (popmax 0.00306%, nfe)

Conditions

esophageal atresia/tracheoesophageal fistula

Computational evidence

Protein change
Missense predictors do not apply to this variant type; conservation carries the signal.
Consequence	nonsense (stop-gain)	predicted loss-of-function
NMD	escapes	premature termination codon in the last exon (2 of 2) — the truncated protein is likely expressed. PVS1 input, not an applied code
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP -0.069	GERP -3.8
Overall
CADD	31.0	PHRED · no single calibrated threshold — expert panels disagree

Predicted loss-of-function is descriptive, not an applied PVS1 code.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00306% European (non-Finnish) · 36/1,175,836 alleles

Filtering AF 0.00224% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00199%

Overall 0.00243% 39/1,607,444 alleles · very rare

Ancestry group	Frequency	1 in
Finnishnot grpmax-eligible	0.00316%	31,694
European (non-Finnish)grpmax	0.00306%	32,662
Remaining individualsnot grpmax-eligible	0.00161%	62,070

Finnish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: AMER3
Protein: p.Arg746Ter
Coding: c.2236C>T
MANE Select: NM_152698
dbSNP: rs768719549
Type: single nucleotide variant
Location: chr2:130764308 (GRCh38)
Structure: AlphaFold pLDDT 45.30

Full AMER3 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

esophageal atresia/tracheoesophageal fistula — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

AMER3 p.Arg746Gln Uncertain significance ★ ⚠ same residue
AMER3 p.Ala175Val Uncertain significance ★ ⚠ same type
AMER3 p.Ala25Thr Uncertain significance ★ ⚠ same type
AMER3 p.Ala345Ser Uncertain significance ★ ⚠ same type
AMER3 p.Ala402Asp Uncertain significance ★ ⚠ same type
AMER3 p.Ala557Thr Uncertain significance ★ ⚠ same type
AMER3 p.Ala55Thr Uncertain significance ★ ⚠ same type
AMER3 p.Ala579Thr 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/amer3-p-arg746ter (accessed [today's date]).

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