Is ICMT p.Ala2Glu (c.5C>A) pathogenic?

ICMT p.Ala2Glu (c.5C>A) is classified Uncertain significance in ICMT (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-03). AlphaMissense: likely benign (0.1316); Very rare (popmax 0.00677%, nfe).

How common is ICMT p.Ala2Glu (c.5C>A) in the general population?

ICMT p.Ala2Glu (c.5C>A) is very rare (popmax 0.00677%, nfe) (gnomAD).

What do computational predictors say about ICMT p.Ala2Glu (c.5C>A)?

AlphaMissense predicts likely benign (score 0.1316) — an in-silico prediction, not a clinical call.

ICMT p.Ala2Glu

c.5C>A · rs1270063541 · VCV3107981

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1316 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00677%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1316	likely benign
REVEL	0.063	moderately benign-leaning
SaProt	LLR -7.68	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 6.5	GERP 0.45, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 938 bp · p 0.51 · regional, not allelic
Overall
CADD	23.3	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 0.00677% European (non-Finnish) · 62/915,310 alleles

Filtering AF 0.00539% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00489%

Overall 0.00583% 65/1,114,480 alleles · very rare exomes 61/968,318 · genomes 4/146,162 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.00677%	14,763
African / African-American	0.00345%	29,016
Remaining individualsnot grpmax-eligible	0.00266%	37,660

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: ICMT
Protein: p.Ala2Glu
Coding: c.5C>A
MANE Select: NM_012405
dbSNP: rs1270063541
Type: single nucleotide variant
Location: chr1:6235907 (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.Ala2Ser Uncertain significance ★ ⚠ same residue
ICMT p.Val188= Benign ★★ same type
ICMT p.Ala176Val Uncertain significance ★ ⚠ same type
ICMT p.Ala19Ser 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
ICMT p.Arg242Gln 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-ala2glu (accessed [today's date]).

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