Is CLTCL1 p.Pro985Arg (c.2954C>G) pathogenic?

CLTCL1 p.Pro985Arg (c.2954C>G) is classified Uncertain significance in CLTCL1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-16). AlphaMissense: likely benign (0.199); Very rare (popmax 0.0011%, sas).

How common is CLTCL1 p.Pro985Arg (c.2954C>G) in the general population?

CLTCL1 p.Pro985Arg (c.2954C>G) is very rare (popmax 0.0011%, sas) (gnomAD).

What do computational predictors say about CLTCL1 p.Pro985Arg (c.2954C>G)?

AlphaMissense predicts likely benign (score 0.199) — an in-silico prediction, not a clinical call.

CLTCL1 p.Pro985Arg

c.2954C>G · VCV4828504

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.199 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0011%, sas)

Missense predictors

1/2 damaging

AlphaMissense, SaProt · REVEL no call

Computational evidence

Protein change
AlphaMissense	0.199	likely benign
REVEL	0.452	indeterminate
SaProt	LLR -11.35	damaging
⇒ SaProt calls this damaging; AlphaMissense does not; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.1	GERP 1.8, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 111 kb · p 0.00057 · regional, not allelic
Overall
CADD	24.3	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 0.0011% South Asian · 1/91,074 alleles

Overall 0.000137% 2/1,461,684 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0011%	91,074
European (non-Finnish)	8.48e-05%	1,179,885

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: CLTCL1
Protein: p.Pro985Arg
Coding: c.2954C>G
MANE Select: NM_007098
Type: single nucleotide variant
Location: chr22:19216222 (GRCh38)
Gene constraint: LOEUF 0.993 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.53
Residue 985: the 'heavy chain arm' region; the 'proximal segment' region

Full CLTCL1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

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CLTCL1 p.Gln1113Lys Uncertain significance ★★ ⚠ same type
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CLTCL1 p.Glu1212Lys Uncertain significance ★★ ⚠ same type
CLTCL1 p.Gly464Arg Uncertain significance ★★ ⚠ same type
CLTCL1 p.Ser1061Gly Uncertain significance ★★ ⚠ same type
CLTCL1 p.Ser707Gly Uncertain significance ★★ ⚠ same type
CLTCL1 p.Val948Gly 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/cltcl1-p-pro985arg (accessed [today's date]).

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