Is CLHC1 p.Pro321Thr (c.961C>A) pathogenic?

CLHC1 p.Pro321Thr (c.961C>A) is classified Uncertain significance in CLHC1 (ClinVar, Single submitter, 1 submitter; last evaluated 2024-11-24). AlphaMissense: ambiguous (0.39); Very rare (popmax 0.00333%, amr).

How common is CLHC1 p.Pro321Thr (c.961C>A) in the general population?

CLHC1 p.Pro321Thr (c.961C>A) is very rare (popmax 0.00333%, amr) (gnomAD).

What do computational predictors say about CLHC1 p.Pro321Thr (c.961C>A)?

AlphaMissense predicts ambiguous (score 0.39) — an in-silico prediction, not a clinical call.

CLHC1 p.Pro321Thr

c.961C>A · VCV3493643

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.39 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00333%, amr)

Computational evidence

Protein change
AlphaMissense	0.39	ambiguous
REVEL	0.409	indeterminate
SaProt	LLR -11.20	damaging
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 1.16	unconstrained · MANE · 47 kb · p 2.2e-05 · regional, not allelic
Overall
CADD	25.1	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 0.00333% Admixed American · 2/59,970 alleles

Filtering AF 0.00173% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00149%

Overall 0.00192% 31/1,611,198 alleles · very rare

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00333%	29,985
European (non-Finnish)	0.00246%	40,620

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: CLHC1
Protein: p.Pro321Thr
Coding: c.961C>A
MANE Select: NM_152385
Type: single nucleotide variant
Location: chr2:55206315 (GRCh38)
Gene constraint: LOEUF 1.186 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 81.85

Full CLHC1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

CLHC1 p.Ala121Thr Uncertain significance ★ ⚠ same type
CLHC1 p.Ala196Val Uncertain significance ★ ⚠ same type
CLHC1 p.Ala336Gly Uncertain significance ★ ⚠ same type
CLHC1 p.Ala367Val Uncertain significance ★ ⚠ same type
CLHC1 p.Ala567Thr Uncertain significance ★ ⚠ same type
CLHC1 p.Arg206Gly Uncertain significance ★ ⚠ same type
CLHC1 p.Arg286Cys Uncertain significance ★ ⚠ same type
CLHC1 p.Arg286Pro 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/clhc1-p-pro321thr (accessed [today's date]).

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