Is SARAF p.Arg40Pro (c.119G>C) pathogenic?

SARAF p.Arg40Pro (c.119G>C) is classified Uncertain significance in SARAF (ClinVar, Single submitter, 1 submitter; last evaluated 2024-08-10). AlphaMissense: likely pathogenic (0.8589); Ultra-rare (popmax 0.0256%, nfe).

How common is SARAF p.Arg40Pro (c.119G>C) in the general population?

SARAF p.Arg40Pro (c.119G>C) is ultra-rare (popmax 0.0256%, nfe) (gnomAD).

What do computational predictors say about SARAF p.Arg40Pro (c.119G>C)?

AlphaMissense predicts likely pathogenic (score 0.8589) — an in-silico prediction, not a clinical call.

SARAF p.Arg40Pro

c.119G>C · VCV3437340

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.8589 · ACMG-weighted

gnomAD v4.1

Rare

ultra-rare (popmax 0.0256%, nfe)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Computational evidence

Protein change
AlphaMissense	0.8589	likely pathogenic
REVEL	0.349	indeterminate
SaProt	LLR -12.96	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 2.7	GERP 0.88, phastCons 1
Regional constraint	o/e 0.92	unconstrained · MANE · 19 kb · p 0.091 · regional, not allelic
Overall
CADD	25.3	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 0.0256% European (non-Finnish) · 302/1,179,544 alleles

Filtering AF 0.0232% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.0223%

Overall 0.0195% 314/1,613,184 alleles · ultra-rare exomes 295/1,461,064 · genomes 19/152,120 · joint denominator

Ancestry group	Frequency	1 in
European (non-Finnish)grpmax	0.0256%	3,906
Remaining individualsnot grpmax-eligible	0.0128%	7,805
Finnishnot grpmax-eligible	0.00312%	32,006
African / African-American	0.00267%	37,431

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: SARAF
Protein: p.Arg40Pro
Coding: c.119G>C
MANE Select: NM_016127
Type: single nucleotide variant
Location: chr8:30074040 (GRCh38)
Gene constraint: LOEUF 0.847 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 68.55 · 3 PDB
Residue 40: an α-helix

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

Similar variants

SARAF p.Ala168Val Uncertain significance ★ ⚠ same type
SARAF p.Ala242Thr Uncertain significance ★ ⚠ same type
SARAF p.Ala282Val Uncertain significance ★ ⚠ same type
SARAF p.Ala283Thr Uncertain significance ★ ⚠ same type
SARAF p.Arg213Cys Uncertain significance ★ ⚠ same type
SARAF p.Arg339Gln Uncertain significance ★ ⚠ same type
SARAF p.Arg51His Uncertain significance ★ ⚠ same type
SARAF p.Asn322Asp 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/saraf-p-arg40pro (accessed [today's date]).

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