Is NMRAL1 p.Arg22Cys (c.64C>T) pathogenic?

NMRAL1 p.Arg22Cys (c.64C>T) is classified Uncertain significance in NMRAL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-09-25). AlphaMissense: likely benign (0.1887); Rare (popmax 0.107%, eas).

How common is NMRAL1 p.Arg22Cys (c.64C>T) in the general population?

NMRAL1 p.Arg22Cys (c.64C>T) is rare (popmax 0.107%, eas) (gnomAD).

What do computational predictors say about NMRAL1 p.Arg22Cys (c.64C>T)?

AlphaMissense predicts likely benign (score 0.1887) — an in-silico prediction, not a clinical call.

NMRAL1 p.Arg22Cys

c.64C>T · rs141993533 · VCV2303274

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1887 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.107%, eas)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1887	likely benign
REVEL	0.215	benign-leaning
SaProt	LLR -11.50	damaging
⇒ SaProt calls this damaging; AlphaMissense and REVEL do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 3	GERP -0.58, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.16 · regional, not allelic
Overall
CADD	23.2	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 0.107% East Asian · 48/44,872 alleles

Filtering AF 0.0829% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0743%

Overall 0.0044% 71/1,613,836 alleles · rare exomes 67/1,461,728 · genomes 4/152,108 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.107%	935
Middle Eastern	0.0165%	6,060
Remaining individualsnot grpmax-eligible	0.0032%	31,246
South Asian	0.0022%	45,536
European (non-Finnish)	0.00153%	65,551

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: NMRAL1
Protein: p.Arg22Cys
Coding: c.64C>T
MANE Select: NM_020677
dbSNP: rs141993533
Type: single nucleotide variant
Location: chr16:4469442 (GRCh38)
Gene constraint: LOEUF 1.471 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.67 · 5 PDB
Residue 22: an α-helix

Full NMRAL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

NMRAL1 p.Ala126Ser Uncertain significance ★ ⚠ same type
NMRAL1 p.Ala127Thr Uncertain significance ★ ⚠ same type
NMRAL1 p.Ala128Thr Uncertain significance ★ ⚠ same type
NMRAL1 p.Ala43Thr Uncertain significance ★ ⚠ same type
NMRAL1 p.Ala43Val Uncertain significance ★ ⚠ same type
NMRAL1 p.Ala68Thr Uncertain significance ★ ⚠ same type
NMRAL1 p.Ala98Thr Uncertain significance ★ same type
NMRAL1 p.Arg141Gln 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/nmral1-p-arg22cys (accessed [today's date]).

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