Is NMRAL1 p.Arg270His (c.809G>A) pathogenic?

NMRAL1 p.Arg270His (c.809G>A) is classified Likely benign in NMRAL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-20). AlphaMissense: ambiguous (0.5173); Very rare (popmax 0.00167%, amr).

How common is NMRAL1 p.Arg270His (c.809G>A) in the general population?

NMRAL1 p.Arg270His (c.809G>A) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about NMRAL1 p.Arg270His (c.809G>A)?

AlphaMissense predicts ambiguous (score 0.5173) — an in-silico prediction, not a clinical call.

NMRAL1 p.Arg270His

c.809G>A · VCV3920516

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.5173 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense indeterminate

Computational evidence

Protein change
AlphaMissense	0.5173	ambiguous
REVEL	0.175	moderately benign-leaning
SaProt	LLR -10.25	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4	GERP 1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.16 · regional, not allelic
Overall
CADD	19.36	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 0.00167% Admixed American · 1/60,016 alleles

Filtering AF 6.8e-05% ClinGen BA1/BS1 input FAF95, joint · FAF99 1.9e-05%

Overall 0.000248% 4/1,614,162 alleles · very rare exomes 4/1,461,860 · genomes 0/152,302 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,016
European (non-Finnish)	0.000254%	393,338

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.Arg270His
Coding: c.809G>A
MANE Select: NM_020677
Type: single nucleotide variant
Location: chr16:4461871 (GRCh38)
Gene constraint: LOEUF 1.471 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.67 · 5 PDB

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

Similar variants

NMRAL1 p.Arg270Leu Uncertain significance ★ ⚠ same residue
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

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-arg270his (accessed [today's date]).

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