Is ARMC2 p.Leu680Ser (c.2039T>C) pathogenic?

ARMC2 p.Leu680Ser (c.2039T>C) is classified Uncertain significance in ARMC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2022-11-18). AlphaMissense: ambiguous (0.3648); Ultra-rare (popmax 0.0324%, amr).

How common is ARMC2 p.Leu680Ser (c.2039T>C) in the general population?

ARMC2 p.Leu680Ser (c.2039T>C) is ultra-rare (popmax 0.0324%, amr) (gnomAD).

What do computational predictors say about ARMC2 p.Leu680Ser (c.2039T>C)?

AlphaMissense predicts ambiguous (score 0.3648) — an in-silico prediction, not a clinical call.

ARMC2 p.Leu680Ser

c.2039T>C · rs199601231 · VCV3129620

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3648 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0324%, amr)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3648	ambiguous
REVEL	0.139	moderately benign-leaning
SaProt	LLR -9.57	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5	GERP 1.9, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 119 kb · p 0.00055 · regional, not allelic
Overall
CADD	27.4	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 0.0324% Admixed American · 18/55,496 alleles

Filtering AF 0.0209% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0172%

Overall 0.00476% 76/1,597,150 alleles · ultra-rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.0324%	3,083
African / African-American	0.00539%	18,547
Remaining individualsnot grpmax-eligible	0.00484%	20,654
European (non-Finnish)	0.00426%	23,468
South Asian	0.00114%	87,418

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: ARMC2
Protein: p.Leu680Ser
Coding: c.2039T>C
MANE Select: NM_032131
dbSNP: rs199601231
Type: single nucleotide variant
Location: chr6:108962014 (GRCh38)
Gene constraint: LOEUF 0.936 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.57
Residue 680: a UniProt-annotated variant site (in spgf38; uncertain significance)

Full ARMC2 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

ARMC2 c.2153-1G>C Likely pathogenic ★ same type
ARMC2 p.Asn743Asp Likely pathogenic ★ same type
ARMC2 p.Ala123Val Uncertain significance ★ ⚠ same type
ARMC2 p.Ala143Thr Uncertain significance ★ ⚠ same type
ARMC2 p.Ala231Thr Uncertain significance ★ ⚠ same type
ARMC2 p.Ala260Pro Uncertain significance ★ ⚠ same type
ARMC2 p.Ala292Asp Uncertain significance ★ ⚠ same type
ARMC2 p.Ala495Val 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/armc2-p-leu680ser (accessed [today's date]).

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