Is MTNR1B p.Arg231His (c.692G>A) pathogenic?

MTNR1B p.Arg231His (c.692G>A) is classified Likely benign in MTNR1B (ClinVar, Single submitter, 1 submitter; last evaluated 2026-02-01). AlphaMissense: likely benign (0.1582); Rare (popmax 0.765%, nfe).

How common is MTNR1B p.Arg231His (c.692G>A) in the general population?

MTNR1B p.Arg231His (c.692G>A) is rare (popmax 0.765%, nfe) (gnomAD).

What do computational predictors say about MTNR1B p.Arg231His (c.692G>A)?

AlphaMissense predicts likely benign (score 0.1582) — an in-silico prediction, not a clinical call.

MTNR1B p.Arg231His

c.692G>A · VCV4820720

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1582 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.765%, nfe)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1582	likely benign
REVEL	0.124	moderately benign-leaning
SaProt	LLR -9.02	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 0.1	GERP -3.9
Regional constraint	o/e 0.98	unconstrained · MANE · 13 kb · p 0.7 · regional, not allelic
Overall
CADD	16.84	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 0.765% European (non-Finnish) · 9,023/1,180,042 alleles

Filtering AF 0.751% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.746%

Overall 0.613% 9,888/1,614,166 alleles · rare

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.765%	131
Finnishnot grpmax-eligible	0.48%	208
Remaining individualsnot grpmax-eligible	0.467%	214
Admixed American	0.173%	577
African / African-American	0.0959%	1,042
South Asian	0.0769%	1,301
Middle Eastern	0.066%	1,516
Ashkenazi Jewishnot grpmax-eligible	0.054%	1,851

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: MTNR1B
Protein: p.Arg231His
Coding: c.692G>A
MANE Select: NM_005959
Type: single nucleotide variant
Location: chr11:92981915 (GRCh38)
Gene constraint: LOEUF 1.917 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 84.75 · 5 PDB
Residue 231: a UniProt-annotated variant site (in)

Full MTNR1B gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

MTNR1B p.Arg231Ser Uncertain significance ★ ⚠ same residue
MTNR1B p.Gly126= Benign ★★ same type
MTNR1B p.Ala100Thr Uncertain significance ★ ⚠ same type
MTNR1B p.Ala117Thr Uncertain significance ★ ⚠ same type
MTNR1B p.Ala203Ser Uncertain significance ★ ⚠ same type
MTNR1B p.Ala234Asp Uncertain significance ★ ⚠ same type
MTNR1B p.Ala265Val Uncertain significance ★ ⚠ same type
MTNR1B p.Ala28Val 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/mtnr1b-p-arg231his (accessed [today's date]).

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