Is ARMC8 p.Glu356Lys (c.1066G>A) pathogenic?

ARMC8 p.Glu356Lys (c.1066G>A) is classified Uncertain significance in ARMC8 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-03). AlphaMissense: likely pathogenic (0.7284); Very rare (popmax 0.00223%, eas).

How common is ARMC8 p.Glu356Lys (c.1066G>A) in the general population?

ARMC8 p.Glu356Lys (c.1066G>A) is very rare (popmax 0.00223%, eas) (gnomAD).

What do computational predictors say about ARMC8 p.Glu356Lys (c.1066G>A)?

AlphaMissense predicts likely pathogenic (score 0.7284) — an in-silico prediction, not a clinical call.

ARMC8 p.Glu356Lys

c.1066G>A · VCV3948080

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7284 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00223%, eas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.7284	likely pathogenic
REVEL	0.382	indeterminate
SaProt	LLR -6.52	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.54	unconstrained · MANE · 54 kb · p 9.7e-21 · regional, not allelic
Overall
CADD	27.3	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 0.00223% East Asian · 1/44,892 alleles

Filtering AF 0.000247% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000159%

Overall 0.000558% 9/1,613,782 alleles · very rare

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00223%	44,892
Admixed American	0.00167%	59,974
European (non-Finnish)	0.000593%	168,568

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: ARMC8
Protein: p.Glu356Lys
Coding: c.1066G>A
MANE Select: NM_001363941
Type: single nucleotide variant
Location: chr3:138245115 (GRCh38)
Gene constraint: LOEUF 0.317 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.16 · 1 PDB
Residue 356: an α-helix

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

Similar variants

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
ARMC8 p.Arg542Cys 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-glu356lys (accessed [today's date]).

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