Is CTTN p.Ser458Arg (c.1374C>G) pathogenic?

CTTN p.Ser458Arg (c.1374C>G) is classified Uncertain significance in CTTN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-08-10). AlphaMissense: likely benign (0.1235); Rare (popmax 0.768%, amr).

How common is CTTN p.Ser458Arg (c.1374C>G) in the general population?

CTTN p.Ser458Arg (c.1374C>G) is rare (popmax 0.768%, amr) (gnomAD).

What do computational predictors say about CTTN p.Ser458Arg (c.1374C>G)?

AlphaMissense predicts likely benign (score 0.1235) — an in-silico prediction, not a clinical call.

CTTN p.Ser458Arg

c.1374C>G · VCV4235930

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.1235 · ACMG-weighted

gnomAD v4.1

Rare

rare (popmax 0.768%, amr)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.1235	likely benign
REVEL	0.094	moderately benign-leaning
SaProt	LLR -7.44	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 0.7	GERP 0.17, phastCons 1
Regional constraint	o/e 1.06	unconstrained · MANE · 12 kb · p 0.34 · regional, not allelic
Overall
CADD	16.27	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 and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.768% Admixed American · 461/60,022 alleles

Filtering AF 0.71% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.687%

Overall 0.0288% 464/1,613,542 alleles · rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.768%	130
Remaining individualsnot grpmax-eligible	0.0032%	31,247
African / African-American	0.00133%	75,054

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: CTTN
Protein: p.Ser458Arg
Coding: c.1374C>G
MANE Select: NM_005231
Type: single nucleotide variant
Location: chr11:70433208 (GRCh38)
Gene constraint: LOEUF 0.48 · pLI 0.99 (gnomAD)
Structure: AlphaFold pLDDT 63.11 · 5 PDB

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

Similar variants

CTTN p.Val312= Benign ★★ same type
CTTN p.Val340Gly Likely benign ★★ same type
CTTN c.*1144C>G Uncertain significance ★ same type
CTTN c.*1145C>T Uncertain significance ★ same type
CTTN c.*1154G>A Uncertain significance ★ same type
CTTN c.*1164C>T Uncertain significance ★ same type
CTTN c.*1167C>T Uncertain significance ★ same type
CTTN c.*1173G>A 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/cttn-p-ser458arg (accessed [today's date]).

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