Is SCTR p.Met219Ile (c.657G>C) pathogenic?

SCTR p.Met219Ile (c.657G>C) is classified Uncertain significance in SCTR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-01-23). AlphaMissense: likely pathogenic (0.6968); Very rare (popmax 0.00937%, afr).

How common is SCTR p.Met219Ile (c.657G>C) in the general population?

SCTR p.Met219Ile (c.657G>C) is very rare (popmax 0.00937%, afr) (gnomAD).

What do computational predictors say about SCTR p.Met219Ile (c.657G>C)?

AlphaMissense predicts likely pathogenic (score 0.6968) — an in-silico prediction, not a clinical call.

SCTR p.Met219Ile

c.657G>C · rs199636057 · VCV3158744

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.6968 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00937%, afr)

Missense predictors

1/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.6968	likely pathogenic
REVEL	0.184	benign-leaning
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense calls this damaging; REVEL and SaProt do not.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 5.8	GERP 2.1, phastCons 1
Regional constraint	o/e 1.02	unconstrained · MANE · 84 kb · p 0.62 · regional, not allelic
Overall
CADD	22.3	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 0.00937% African / African-American · 7/74,716 alleles

Filtering AF 0.00438% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00309%

Overall 0.000747% 12/1,606,720 alleles · very rare exomes 9/1,454,414 · genomes 3/152,306 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00937%	10,674
East Asian	0.0045%	22,234
Remaining individualsnot grpmax-eligible	0.00322%	31,095
Admixed American	0.0017%	58,954

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.Met219Ile
Coding: c.657G>C
MANE Select: NM_002980
dbSNP: rs199636057
Type: single nucleotide variant
Location: chr2:119461980 (GRCh38)
Gene constraint: LOEUF 1.373 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 77.18 · 3 PDB
Residue 219: 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-met219ile (accessed [today's date]).

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