Is CMIP p.Leu685Arg (c.2054T>G) pathogenic?

CMIP p.Leu685Arg (c.2054T>G) is classified Uncertain significance in CMIP (ClinVar, Single submitter, 1 submitter; last evaluated 2021-12-08). AlphaMissense: likely pathogenic (0.9963); Absent from gnomAD v4.1.

How common is CMIP p.Leu685Arg (c.2054T>G) in the general population?

CMIP p.Leu685Arg (c.2054T>G) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about CMIP p.Leu685Arg (c.2054T>G)?

AlphaMissense predicts likely pathogenic (score 0.9963) — an in-silico prediction, not a clinical call.

CMIP p.Leu685Arg

c.2054T>G · rs2509250847 · VCV2263011

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9963 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9963	likely pathogenic
REVEL	0.795	moderately pathogenic-leaning
SaProt	LLR -14.32	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 7.8	GERP 1.2, phastCons 1
Regional constraint	o/e 0.69	unconstrained · MANE · 18 kb · p 1.7e-09 · regional, not allelic
Overall
CADD	33.0	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: CMIP
Protein: p.Leu685Arg
Coding: c.2054T>G
MANE Select: NM_198390
dbSNP: rs2509250847
Type: single nucleotide variant
Location: chr16:81704048 (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

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-leu685arg (accessed [today's date]).

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