Is UTRN p.Arg657His (c.1970G>A) pathogenic?

UTRN p.Arg657His (c.1970G>A) is classified Uncertain significance in UTRN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-01-21). AlphaMissense: likely benign (0.0686); Very rare (popmax 0.00439%, sas).

How common is UTRN p.Arg657His (c.1970G>A) in the general population?

UTRN p.Arg657His (c.1970G>A) is very rare (popmax 0.00439%, sas) (gnomAD).

What do computational predictors say about UTRN p.Arg657His (c.1970G>A)?

AlphaMissense predicts likely benign (score 0.0686) — an in-silico prediction, not a clinical call.

UTRN p.Arg657His

c.1970G>A · VCV3814604

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0686 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00439%, sas)

Missense predictors

0/2 damaging

AlphaMissense, REVEL · SaProt no call

Computational evidence

Protein change
AlphaMissense	0.0686	likely benign
REVEL	0.034	moderately benign-leaning
SaProt	—	not scored · why
⇒ AlphaMissense and REVEL both call this tolerated; SaProt makes no call.
Splicing
SpliceAI	Δ0.35	donor gain · deltas
Constraint at this position
Conservation	phyloP 3.1	GERP -4.2, phastCons 0.99
Regional constraint	o/e 1.02	unconstrained · MANE · 119 kb · p 0.35 · regional, not allelic
Overall
CADD	18.65	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 is an independent agreement signal.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00439% South Asian · 4/91,078 alleles

Filtering AF 0.00143% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00108%

Overall 0.00192% 31/1,613,984 alleles · very rare

Ancestry group	Frequency	1 in
Remaining individualsnot grpmax-eligible	0.0048%	20,833
South Asiangrpmax	0.00439%	22,769
European (non-Finnish)	0.00195%	51,302
African / African-American	0.00133%	75,000

Remaining individuals shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

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: UTRN
Protein: p.Arg657His
Coding: c.1970G>A
MANE Select: NM_007124
Type: single nucleotide variant
Location: chr6:144448667 (GRCh38)
Gene constraint: LOEUF 0.665 · pLI <0.01 (gnomAD)
Residue 657: the 'interaction with synm' region

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

Similar variants

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UTRN p.Arg1967Trp Benign/Likely benign ★★ same type
UTRN p.Gly1862Glu Likely benign ★★ same type
UTRN p.Ile2227Val Likely benign ★★ same type
UTRN p.Ser1561Cys Likely benign ★★ same type
UTRN p.Thr2288= Likely benign ★★ 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/utrn-p-arg657his (accessed [today's date]).

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