Is SAMD9 p.Ser678Pro (c.2032T>C) pathogenic?

SAMD9 p.Ser678Pro (c.2032T>C) is classified Uncertain significance in SAMD9 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-08-01). AlphaMissense: ambiguous (0.5226); Very rare (popmax 0.000424%, nfe).

How common is SAMD9 p.Ser678Pro (c.2032T>C) in the general population?

SAMD9 p.Ser678Pro (c.2032T>C) is very rare (popmax 0.000424%, nfe) (gnomAD).

What do computational predictors say about SAMD9 p.Ser678Pro (c.2032T>C)?

AlphaMissense predicts ambiguous (score 0.5226) — an in-silico prediction, not a clinical call.

SAMD9 p.Ser678Pro

c.2032T>C · rs766374544 · VCV1436391

Uncertain significance Multiple submitters

Classification

Uncertain significance

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 2 submitters

AlphaMissense

ambiguous

0.5226 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.000424%, nfe)

Missense predictors

1/2 damaging

REVEL, SaProt · AlphaMissense no call

Computational evidence

Protein change
AlphaMissense	0.5226	ambiguous
REVEL	0.05	moderately benign-leaning
SaProt	LLR -10.74	damaging
⇒ SaProt calls this damaging; REVEL does not; AlphaMissense makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 1.4
Regional constraint	o/e 0.78	unconstrained · MANE · 1,217 bp · p 1.8e-06 · regional, not allelic
Overall
CADD	15.96	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 0.000424% European (non-Finnish) · 5/1,179,868 alleles

Filtering AF 0.000124% ClinGen BA1/BS1 input FAF95, joint · FAF99 9e-05%

Overall 0.00031% 5/1,613,972 alleles · very rare exomes 5/1,461,726 · genomes 0/152,246 · joint denominator

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: SAMD9
Protein: p.Ser678Pro
Coding: c.2032T>C
MANE Select: NM_017654
dbSNP: rs766374544
Type: single nucleotide variant
Location: chr7:93104066 (GRCh38)
Gene constraint: LOEUF 1.773 · pLI 0.03 · ClinGen HI 0/3 (gnomAD)
Structure: AlphaFold pLDDT 83.79 · 10 PDB

Full SAMD9 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Similar variants

SAMD9 p.Ser678Leu Uncertain significance ★ ⚠ same residue
SAMD9 p.Ser678= Likely benign ★ same residue
SAMD9 p.Arg1293Trp Pathogenic ★★ ⚠ same type
SAMD9 p.Arg459Gln Pathogenic ★★ ⚠ same type
SAMD9 p.Arg685Gln Pathogenic/Likely pathogenic ★★ ⚠ same type
SAMD9 p.Arg824Gln Pathogenic ★★ ⚠ same type
SAMD9 p.Arg982Cys Pathogenic/Likely pathogenic ★★ ⚠ same type
SAMD9 p.Arg982His Pathogenic/Likely pathogenic ★★ ⚠ 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/samd9-p-ser678pro (accessed [today's date]).

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