Is CLSPN p.Met1226Val (c.3676A>G) pathogenic?

CLSPN p.Met1226Val (c.3676A>G) is classified Likely benign in CLSPN (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-03). AlphaMissense: likely benign (0.0467); Ultra-rare (popmax 0.0121%, sas).

How common is CLSPN p.Met1226Val (c.3676A>G) in the general population?

CLSPN p.Met1226Val (c.3676A>G) is ultra-rare (popmax 0.0121%, sas) (gnomAD).

What do computational predictors say about CLSPN p.Met1226Val (c.3676A>G)?

AlphaMissense predicts likely benign (score 0.0467) — an in-silico prediction, not a clinical call.

CLSPN p.Met1226Val

c.3676A>G · VCV3834151

Likely benign Single submitter

Classification

Likely benign

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.0467 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0121%, sas)

Missense predictors

0/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.0467	likely benign
REVEL	0.02	moderately benign-leaning
SaProt	LLR -4.47	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 -0.12	GERP -1.1, phastCons 0.001
Regional constraint	o/e 1.00	unconstrained · MANE · 2,657 bp · p 0.97 · regional, not allelic
Overall
CADD	5.002	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 0.0121% South Asian · 11/91,070 alleles

Filtering AF 0.00676% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00522%

Overall 0.00651% 105/1,613,438 alleles · ultra-rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0121%	8,279
African / African-American	0.0107%	9,365
Ashkenazi Jewishnot grpmax-eligible	0.00676%	14,800
European (non-Finnish)	0.0067%	14,931
Remaining individualsnot grpmax-eligible	0.0064%	15,621
East Asian	0.00223%	44,880

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: CLSPN
Protein: p.Met1226Val
Coding: c.3676A>G
MANE Select: NM_022111
Type: single nucleotide variant
Location: chr1:35737410 (GRCh38)
Gene constraint: LOEUF 0.511 · pLI 0.38 (gnomAD)
Structure: AlphaFold pLDDT 51.32 · 5 PDB

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

Similar variants

CLSPN p.Lys338= Benign ★★ same type
CLSPN p.Ala1222Asp Uncertain significance ★ ⚠ same type
CLSPN p.Ala126Val Uncertain significance ★ ⚠ same type
CLSPN p.Ala1295Val Uncertain significance ★ ⚠ same type
CLSPN p.Ala379Val Uncertain significance ★ ⚠ same type
CLSPN p.Ala450Thr Uncertain significance ★ ⚠ same type
CLSPN p.Ala543Pro Uncertain significance ★ ⚠ same type
CLSPN p.Ala578Thr 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/clspn-p-met1226val (accessed [today's date]).

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