Is CCSAP p.Met12Arg (c.35T>G) pathogenic?

CCSAP p.Met12Arg (c.35T>G) is classified Uncertain significance in CCSAP (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-20). AlphaMissense: ambiguous (0.3723); Very rare (popmax 0.00161%, sas).

How common is CCSAP p.Met12Arg (c.35T>G) in the general population?

CCSAP p.Met12Arg (c.35T>G) is very rare (popmax 0.00161%, sas) (gnomAD).

What do computational predictors say about CCSAP p.Met12Arg (c.35T>G)?

AlphaMissense predicts ambiguous (score 0.3723) — an in-silico prediction, not a clinical call.

CCSAP p.Met12Arg

c.35T>G · VCV3997816

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

ambiguous

0.3723 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00161%, sas)

Missense predictors

0/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.3723	ambiguous
REVEL	0.19	benign-leaning
SaProt	LLR -5.30	tolerated
⇒ REVEL and SaProt both call this tolerated; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.2	GERP -2, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 17 kb · p 0.13 · regional, not allelic
Overall
CADD	21.6	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 0.00161% South Asian · 1/62,024 alleles

Filtering AF 0.000136% ClinGen BA1/BS1 input FAF95, joint · FAF99 9.9e-05%

Overall 0.000475% 6/1,264,308 alleles · very rare

Ancestry group	Frequency	1 in
South Asiangrpmax	0.00161%	62,024
European (non-Finnish)	0.000464%	215,609

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: CCSAP
Protein: p.Met12Arg
Coding: c.35T>G
MANE Select: NM_145257
Type: single nucleotide variant
Location: chr1:229342431 (GRCh38)
Gene constraint: LOEUF 1.472 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 64.61

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

Similar variants

CCSAP p.Ala113Thr Uncertain significance ★ ⚠ same type
CCSAP p.Ala208Thr Uncertain significance ★ ⚠ same type
CCSAP p.Arg14His Uncertain significance ★ ⚠ same type
CCSAP p.Arg152Gln Uncertain significance ★ ⚠ same type
CCSAP p.Arg224Gly Uncertain significance ★ ⚠ same type
CCSAP p.Arg235Ser Uncertain significance ★ ⚠ same type
CCSAP p.Arg37Cys Uncertain significance ★ ⚠ same type
CCSAP p.Asp115Glu 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/ccsap-p-met12arg (accessed [today's date]).

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