Is ARMC2 p.Arg91His (c.272G>A) pathogenic?

ARMC2 p.Arg91His (c.272G>A) is classified Uncertain significance in ARMC2 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-05). AlphaMissense: likely benign (0.1686); Ultra-rare (popmax 0.0827%, sas).

How common is ARMC2 p.Arg91His (c.272G>A) in the general population?

ARMC2 p.Arg91His (c.272G>A) is ultra-rare (popmax 0.0827%, sas) (gnomAD).

What do computational predictors say about ARMC2 p.Arg91His (c.272G>A)?

AlphaMissense predicts likely benign (score 0.1686) — an in-silico prediction, not a clinical call.

ARMC2 p.Arg91His

c.272G>A · VCV4146595

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1686 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0827%, sas)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.1686	likely benign
REVEL	0.293	indeterminate
SaProt	LLR -7.33	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.7, phastCons 1
Regional constraint	o/e 0.89	unconstrained · MANE · 119 kb · p 0.00055 · regional, not allelic
Overall
CADD	31.0	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 0.0827% South Asian · 75/90,680 alleles

Filtering AF 0.0676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.062%

Overall 0.00596% 96/1,609,542 alleles · ultra-rare exomes 90/1,457,358 · genomes 6/152,184 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0827%	1,209
Remaining individualsnot grpmax-eligible	0.00321%	31,138
East Asian	0.00224%	44,708
Admixed American	0.00167%	59,866
Finnishnot grpmax-eligible	0.00157%	63,774
European (non-Finnish)	0.00136%	73,554

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.Arg91His
Coding: c.272G>A
MANE Select: NM_032131
Type: single nucleotide variant
Location: chr6:108858252 (GRCh38)
Gene constraint: LOEUF 0.936 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 75.57
Residue 91: the 'disordered' region

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

Similar variants

ARMC2 p.Arg91Cys Uncertain significance ★ ⚠ same residue
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

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-arg91his (accessed [today's date]).

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