Is SRRT p.Arg865Trp (c.2593C>T) pathogenic?

SRRT p.Arg865Trp (c.2593C>T) is classified Uncertain significance in SRRT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-05-01). AlphaMissense: likely pathogenic (0.9718); Very rare (popmax 0.00445%, eas).

How common is SRRT p.Arg865Trp (c.2593C>T) in the general population?

SRRT p.Arg865Trp (c.2593C>T) is very rare (popmax 0.00445%, eas) (gnomAD).

What do computational predictors say about SRRT p.Arg865Trp (c.2593C>T)?

AlphaMissense predicts likely pathogenic (score 0.9718) — an in-silico prediction, not a clinical call.

SRRT p.Arg865Trp

c.2593C>T · VCV3962340

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9718 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00445%, eas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.9718	likely pathogenic
REVEL	0.349	indeterminate
SaProt	LLR -12.46	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 4.9	GERP 1.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 805 bp · p 0.4 · regional, not allelic
Overall
CADD	27.9	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00445% East Asian · 2/44,894 alleles

Filtering AF 0.000803% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.00065%

Overall 0.00124% 20/1,614,074 alleles · very rare exomes 18/1,461,882 · genomes 2/152,192 · joint denominator

Ancestry group	Frequency	1 in
East Asiangrpmax	0.00445%	22,447
Admixed American	0.00167%	59,992
European (non-Finnish)	0.00136%	73,753
African / African-American	0.00133%	74,926

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: SRRT
Protein: p.Arg865Trp
Coding: c.2593C>T
MANE Select: NM_015908
Type: single nucleotide variant
Location: chr7:100888511 (GRCh38)
Gene constraint: LOEUF 0.404 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.61 · 6 PDB

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

Similar variants

SRRT c.1042-18C>G Benign ★★ same type
SRRT c.1042-7C>T Benign ★★ same type
SRRT c.2556-9A>T Benign ★★ same type
SRRT p.Arg518= Benign ★★ same type
SRRT p.Glu205= Benign ★★ same type
SRRT p.Leu157= Benign ★★ same type
SRRT p.Leu265= Benign ★★ same type
SRRT p.Ala190Val 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/srrt-p-arg865trp (accessed [today's date]).

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