Is ICMT p.Cys4Ser (c.11G>C) pathogenic?

ICMT p.Cys4Ser (c.11G>C) is classified Uncertain significance in ICMT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-22). AlphaMissense: likely benign (0.0826); No allele count reported in gnomAD v4.1 (AN 1,120,066).

How common is ICMT p.Cys4Ser (c.11G>C) in the general population?

ICMT p.Cys4Ser (c.11G>C) is no allele count reported in gnomAD v4.1 (AN 1,120,066) (gnomAD).

What do computational predictors say about ICMT p.Cys4Ser (c.11G>C)?

AlphaMissense predicts likely benign (score 0.0826) — an in-silico prediction, not a clinical call.

ICMT p.Cys4Ser

c.11G>C · VCV4273376

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0826 · ACMG-weighted

gnomAD v4.1

Not reported

no allele count reported in gnomAD v4.1 (AN 1,120,066)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0826	likely benign
REVEL	0.043	moderately benign-leaning
SaProt	LLR -3.23	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 4.4	GERP 0.13, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 938 bp · p 0.51 · regional, not allelic
Overall
CADD	19.24	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

No allele count reported in gnomAD v4.1 (AN 1,120,066). This is missing data, not an absence: the variant may or may not be present in gnomAD. Rarity (ACMG PM2) and BA1/BS1 cannot be assessed for it.

Variant & gene context

Gene: ICMT
Protein: p.Cys4Ser
Coding: c.11G>C
MANE Select: NM_012405
Type: single nucleotide variant
Location: chr1:6235901 (GRCh38)
Gene constraint: LOEUF 0.604 · pLI 0.74 (gnomAD)
Structure: AlphaFold pLDDT 93.57

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

Similar variants

ICMT p.Val188= Benign ★★ same type
ICMT p.Ala176Val Uncertain significance ★ ⚠ same type
ICMT p.Ala19Ser Uncertain significance ★ ⚠ same type
ICMT p.Ala2Glu Uncertain significance ★ ⚠ same type
ICMT p.Ala2Ser Uncertain significance ★ ⚠ same type
ICMT p.Ala36Thr Uncertain significance ★ ⚠ same type
ICMT p.Ala6Ser Uncertain significance ★ ⚠ same type
ICMT p.Arg209Gln 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/icmt-p-cys4ser (accessed [today's date]).

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