Is SCTR p.Met145Ile (c.435G>A) pathogenic?

SCTR p.Met145Ile (c.435G>A) is classified Uncertain significance in SCTR (ClinVar, Single submitter, 1 submitter; last evaluated 2023-11-20). AlphaMissense: likely pathogenic (0.5685); Ultra-rare (popmax 0.0155%, nfe).

How common is SCTR p.Met145Ile (c.435G>A) in the general population?

SCTR p.Met145Ile (c.435G>A) is ultra-rare (popmax 0.0155%, nfe) (gnomAD).

What do computational predictors say about SCTR p.Met145Ile (c.435G>A)?

AlphaMissense predicts likely pathogenic (score 0.5685) — an in-silico prediction, not a clinical call.

SCTR p.Met145Ile

c.435G>A · rs756009251 · VCV3158743

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.5685 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0155%, nfe)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.5685	likely pathogenic
REVEL	0.27	benign-leaning
SaProt	LLR -3.81	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 4.7	GERP -0.066, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 84 kb · p 0.62 · regional, not allelic
Overall
CADD	19.89	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 0.0155% European (non-Finnish) · 183/1,179,948 alleles

Filtering AF 0.0137% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0129%

Overall 0.0118% 190/1,613,930 alleles · ultra-rare exomes 181/1,461,766 · genomes 9/152,164 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0155%	6,448
Remaining individualsnot grpmax-eligible	0.008%	12,496
Ashkenazi Jewishnot grpmax-eligible	0.00338%	29,606
African / African-American	0.00133%	74,908

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: SCTR
Protein: p.Met145Ile
Coding: c.435G>A
MANE Select: NM_002980
dbSNP: rs756009251
Type: single nucleotide variant
Location: chr2:119465857 (GRCh38)
Gene constraint: LOEUF 1.373 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.18 · 3 PDB
Residue 145: an α-helix

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

Similar variants

SCTR c.851+10C>T Benign ★★ same type
SCTR p.Ala292Thr Likely benign ★★ same type
SCTR p.Asp110Asn Benign ★★ same type
SCTR p.Cys208= Benign ★★ same type
SCTR p.Leu190= Benign ★★ same type
SCTR p.Pro415= Benign ★★ same type
SCTR p.Ala245Thr Uncertain significance ★ ⚠ same type
SCTR p.Ala375Val 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/sctr-p-met145ile (accessed [today's date]).

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