Is ARMC5 p.Ser266Thr (c.797G>C) pathogenic?

ARMC5 p.Ser266Thr (c.797G>C) is classified Uncertain significance in ARMC5 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2022-11-16). AlphaMissense: likely benign (0.1393); Very rare (popmax 0.00314%, nfe); Associated with Inborn genetic diseases.

What condition is associated with ARMC5 p.Ser266Thr (c.797G>C)?

ARMC5 p.Ser266Thr (c.797G>C) is associated with Inborn genetic diseases (ClinVar).

How common is ARMC5 p.Ser266Thr (c.797G>C) in the general population?

ARMC5 p.Ser266Thr (c.797G>C) is very rare (popmax 0.00314%, nfe) (gnomAD).

What do computational predictors say about ARMC5 p.Ser266Thr (c.797G>C)?

AlphaMissense predicts likely benign (score 0.1393) — an in-silico prediction, not a clinical call.

ARMC5 p.Ser266Thr

c.797G>C · rs377085139 · VCV2260845

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

likely benign

0.1393 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00314%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.1393	likely benign
REVEL	0.088	moderately benign-leaning
SaProt	LLR -3.46	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 12	GERP 1, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 4,961 bp · p 1.6e-10 · regional, not allelic
Overall
CADD	20.2	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 0.00314% European (non-Finnish) · 37/1,178,878 alleles

Filtering AF 0.00232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00202%

Overall 0.00248% 40/1,610,422 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.00481%	20,779
European (non-Finnish)grpmax	0.00314%	31,862

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: ARMC5
Protein: p.Ser266Thr
Coding: c.797G>C
MANE Select: NM_001105247
dbSNP: rs377085139
Type: single nucleotide variant
Location: chr16:31462344 (GRCh38)
Gene constraint: LOEUF 0.772 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.27
Residue 266: a UniProt-annotated variant site (in aimah2; uncertain significance); a UniProt-annotated variant site (in aimah2)

Full ARMC5 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

ARMC5 p.Ala55Val Uncertain significance ★★ ⚠ same condition
ARMC5 p.Arg611Leu Uncertain significance ★★ ⚠ same condition
ARMC5 p.Trp801Cys Uncertain significance ★★ ⚠ same condition
ARMC5 p.Ala100Thr Uncertain significance ★ ⚠ same condition
ARMC5 p.Ala206Ser Uncertain significance ★ ⚠ same condition
ARMC5 p.Ala22Val Uncertain significance ★ ⚠ same condition
ARMC5 p.Ala243Gly Uncertain significance ★ ⚠ same condition
ARMC5 p.Ala252Thr Uncertain significance ★ ⚠ same condition

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/armc5-p-ser266thr (accessed [today's date]).

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