Is CMIP p.Thr493Ser (c.1478C>G) pathogenic?

CMIP p.Thr493Ser (c.1478C>G) is classified Uncertain significance in CMIP (ClinVar, No assertion criteria, 1 submitter; last evaluated 2019-05-22). AlphaMissense: likely pathogenic (0.5981); Very rare (popmax 8.48e-05%, nfe); Associated with esophageal atresia.

What condition is associated with CMIP p.Thr493Ser (c.1478C>G)?

CMIP p.Thr493Ser (c.1478C>G) is associated with esophageal atresia, pyloric stenosis (ClinVar).

How common is CMIP p.Thr493Ser (c.1478C>G) in the general population?

CMIP p.Thr493Ser (c.1478C>G) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CMIP p.Thr493Ser (c.1478C>G)?

AlphaMissense predicts likely pathogenic (score 0.5981) — an in-silico prediction, not a clinical call.

CMIP p.Thr493Ser

c.1478C>G · rs1597258512 · VCV691425

Uncertain significance No assertion criteria

Classification

Uncertain significance

ClinVar

Review

No assertion criteria ☆☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5981 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

esophageal atresia

Computational evidence

Protein change
AlphaMissense	0.5981	likely pathogenic
REVEL	0.261	benign-leaning
SaProt	LLR -7.36	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.7	GERP 2.5, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 18 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	24.0	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 8.48e-05% European (non-Finnish) · 1/1,179,070 alleles

Overall 6.85e-05% 1/1,460,536 alleles · very rare

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: CMIP
Protein: p.Thr493Ser
Coding: c.1478C>G
MANE Select: NM_198390
dbSNP: rs1597258512
Type: single nucleotide variant
Location: chr16:81693181 (GRCh38)
Gene constraint: LOEUF 0.189 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 79.52

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

Disease context

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

Also linked: pyloric stenosis

Similar variants

CMIP c.1638+10G>A Likely benign ★★ same type
CMIP c.2269-10C>T Benign/Likely benign ★★ same type
CMIP p.Asn295= Benign ★★ same type
CMIP p.Leu369= Likely benign ★★ same type
CMIP p.Pro414= Benign ★★ same type
CMIP p.Val547= Benign ★★ same type
CMIP c.1035-1G>A Uncertain significance ★ same type
CMIP p.Ala113Thr 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/cmip-p-thr493ser (accessed [today's date]).

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