Is NMRAL1 p.Met185Thr (c.554T>C) pathogenic?

NMRAL1 p.Met185Thr (c.554T>C) is classified Uncertain significance in NMRAL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2023-03-13). AlphaMissense: likely pathogenic (0.572); Very rare (popmax 0.000254%, nfe).

How common is NMRAL1 p.Met185Thr (c.554T>C) in the general population?

NMRAL1 p.Met185Thr (c.554T>C) is very rare (popmax 0.000254%, nfe) (gnomAD).

What do computational predictors say about NMRAL1 p.Met185Thr (c.554T>C)?

AlphaMissense predicts likely pathogenic (score 0.572) — an in-silico prediction, not a clinical call.

NMRAL1 p.Met185Thr

c.554T>C · rs2505644171 · VCV2454455

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.572 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000254%, nfe)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.572	likely pathogenic
REVEL	0.331	indeterminate
SaProt	LLR -8.25	tolerated
⇒ AlphaMissense calls this damaging; SaProt does not; REVEL is indeterminate.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 11	GERP 2.1, phastCons 1
Regional constraint	o/e 1.07	unconstrained · MANE · 12 kb · p 0.16 · regional, not allelic
Overall
CADD	25.0	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 0.000254% European (non-Finnish) · 3/1,179,816 alleles

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

Overall 0.000186% 3/1,613,726 alleles · very rare exomes 3/1,461,406 · genomes 0/152,320 · joint denominator

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.Met185Thr
Coding: c.554T>C
MANE Select: NM_020677
dbSNP: rs2505644171
Type: single nucleotide variant
Location: chr16:4463826 (GRCh38)
Gene constraint: LOEUF 1.471 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 96.67 · 5 PDB
Residue 185: the 'interaction with ass1' region; a β-strand

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-met185thr (accessed [today's date]).

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