Is ARMC8 p.Met666Ile (c.1998G>C) pathogenic?

ARMC8 p.Met666Ile (c.1998G>C) is classified Uncertain significance in ARMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2021-03-16). AlphaMissense: likely benign (0.179); Absent from gnomAD v4.1.

How common is ARMC8 p.Met666Ile (c.1998G>C) in the general population?

ARMC8 p.Met666Ile (c.1998G>C) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about ARMC8 p.Met666Ile (c.1998G>C)?

AlphaMissense predicts likely benign (score 0.179) — an in-silico prediction, not a clinical call.

ARMC8 p.Met666Ile

c.1998G>C · rs2108410001 · VCV1331617

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.179 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.179	likely benign
REVEL	0.073	moderately benign-leaning
SaProt	LLR -5.12	tolerated
⇒ AlphaMissense, REVEL and SaProt all call this tolerated.
Splicing
SpliceAI	<0.2	all four deltas below 0.2 · G>A here scores Δ0.21 · evaluated, not missing
Constraint at this position
Conservation	phyloP 0.81	GERP -2.4, phastCons 0.99
Regional constraint	o/e 0.54	unconstrained · MANE · 54 kb · p 9.7e-21 · regional, not allelic
Overall
CADD	17.53	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

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: ARMC8
Protein: p.Met666Ile
Coding: c.1998G>C
MANE Select: NM_001363941
dbSNP: rs2108410001
Type: single nucleotide variant
Location: chr3:138295868 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.16 · 1 PDB
Residue 666: an α-helix

Full ARMC8 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARMC8 p.Met666Val Uncertain significance ★ ⚠ same residue
ARMC8 p.Ala403Thr Uncertain significance ★ ⚠ same type
ARMC8 p.Ala469Thr Uncertain significance ★ ⚠ same type
ARMC8 p.Arg159Lys Uncertain significance ★ ⚠ same type
ARMC8 p.Arg161His Uncertain significance ★ ⚠ same type
ARMC8 p.Arg270Gln Uncertain significance ★ ⚠ same type
ARMC8 p.Arg270Trp Uncertain significance ★ ⚠ same type
ARMC8 p.Arg376Trp 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/armc8-p-met666ile (accessed [today's date]).

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