Is SRRT p.Phe839Leu (c.2515T>C) pathogenic?

SRRT p.Phe839Leu (c.2515T>C) is classified Uncertain significance in SRRT (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-24). AlphaMissense: likely pathogenic (0.9809); Very rare (popmax 0.00167%, amr).

How common is SRRT p.Phe839Leu (c.2515T>C) in the general population?

SRRT p.Phe839Leu (c.2515T>C) is very rare (popmax 0.00167%, amr) (gnomAD).

What do computational predictors say about SRRT p.Phe839Leu (c.2515T>C)?

AlphaMissense predicts likely pathogenic (score 0.9809) — an in-silico prediction, not a clinical call.

SRRT p.Phe839Leu

c.2515T>C · VCV4175248

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9809 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00167%, amr)

Missense predictors

2/3 damaging

AlphaMissense, REVEL, SaProt

Computational evidence

Protein change
AlphaMissense	0.9809	likely pathogenic
REVEL	0.675	pathogenic-leaning
SaProt	LLR -7.03	tolerated
⇒ AlphaMissense and REVEL call this damaging; SaProt does not.
Splicing
SpliceAI	<0.2	no splice effect predicted · four deltas, not one · how we know
Constraint at this position
Conservation	phyloP 7.9	GERP 2.6, phastCons 1
Regional constraint	o/e 0.94	unconstrained · MANE · 805 bp · p 0.4 · regional, not allelic
Overall
CADD	29.3	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 0.00167% Admixed American · 1/60,004 alleles

Overall 0.000124% 2/1,613,988 alleles · very rare exomes 1/1,461,786 · genomes 1/152,202 · joint denominator

Ancestry group	Frequency	1 in
Admixed Americangrpmax	0.00167%	60,004
European (non-Finnish)	8.47e-05%	1,179,954

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: SRRT
Protein: p.Phe839Leu
Coding: c.2515T>C
MANE Select: NM_015908
Type: single nucleotide variant
Location: chr7:100888343 (GRCh38)
Gene constraint: LOEUF 0.404 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 66.61 · 6 PDB
Residue 839: the 'disordered' region

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-phe839leu (accessed [today's date]).

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