Is CS p.Arg440Gln (c.1319G>A) pathogenic?

CS p.Arg440Gln (c.1319G>A) is classified Uncertain significance in CS (ClinVar, Single submitter, 1 submitter; last evaluated 2023-05-17). AlphaMissense: likely pathogenic (0.8926); Very rare (popmax 8.48e-05%, nfe).

How common is CS p.Arg440Gln (c.1319G>A) in the general population?

CS p.Arg440Gln (c.1319G>A) is very rare (popmax 8.48e-05%, nfe) (gnomAD).

What do computational predictors say about CS p.Arg440Gln (c.1319G>A)?

AlphaMissense predicts likely pathogenic (score 0.8926) — an in-silico prediction, not a clinical call.

CS p.Arg440Gln

c.1319G>A · rs2547163480 · VCV2547458

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8926 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 8.48e-05%, nfe)

Missense predictors

3/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.8926	likely pathogenic
REVEL	0.881	moderately pathogenic-leaning
SaProt	LLR -14.23	damaging
⇒ AlphaMissense, REVEL and SaProt all call this damaging.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.9	GERP 1.7, phastCons 1
Regional constraint	o/e 0.44	unconstrained · MANE · 13 kb · p 7.5e-36 · regional, not allelic
Overall
CADD	26.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — 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 8.48e-05% European (non-Finnish) · 1/1,179,684 alleles

Overall 6.2e-05% 1/1,613,758 alleles · very rare exomes 1/1,461,488 · genomes 0/152,270 · 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: CS
Protein: p.Arg440Gln
Coding: c.1319G>A
MANE Select: NM_004077
dbSNP: rs2547163480
Type: single nucleotide variant
Location: chr12:56273166 (GRCh38)
Gene constraint: LOEUF 0.356 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 94.56 · 11 PDB
Residue 440: an α-helix

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

Similar variants

CS p.Leu257= Benign ★★ same type
CS p.Phe96= Benign ★★ same type
CS p.Ala2Gly Uncertain significance ★ ⚠ same type
CS p.Ala8Ser Uncertain significance ★ ⚠ same type
CS p.Arg183Gly Uncertain significance ★ ⚠ same type
CS p.Arg191Gln Uncertain significance ★ ⚠ same type
CS p.Arg218Gln Uncertain significance ★ ⚠ same type
CS p.Arg329Gln 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/cs-p-arg440gln (accessed [today's date]).

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