Is SRGAP1 p.Arg240Trp (c.718C>T) pathogenic?

SRGAP1 p.Arg240Trp (c.718C>T) is classified Uncertain significance in SRGAP1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-03-28). AlphaMissense: likely pathogenic (0.9806); Very rare (popmax 0.0022%, sas); Associated with thyroid cancer, nonmedullary, 2.

What condition is associated with SRGAP1 p.Arg240Trp (c.718C>T)?

SRGAP1 p.Arg240Trp (c.718C>T) is associated with thyroid cancer, nonmedullary, 2 (ClinVar).

How common is SRGAP1 p.Arg240Trp (c.718C>T) in the general population?

SRGAP1 p.Arg240Trp (c.718C>T) is very rare (popmax 0.0022%, sas) (gnomAD).

What do computational predictors say about SRGAP1 p.Arg240Trp (c.718C>T)?

AlphaMissense predicts likely pathogenic (score 0.9806) — an in-silico prediction, not a clinical call.

SRGAP1 p.Arg240Trp

Q: How is Familial papillary or follicular thyroid carcinoma inherited?

Typically Not applicable (Orphanet). A genetic counselor can assess individual risk for a family.

c.718C>T · VCV4293338

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.9806 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.0022%, sas)

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

thyroid cancer, nonmedullary, 2

Computational evidence

Protein change
AlphaMissense	0.9806	likely pathogenic
REVEL	0.39	indeterminate
SaProt	LLR -15.65	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 3.4	GERP 1.7, phastCons 1
Regional constraint	o/e 0.80	unconstrained · MANE · 281 kb · p 2.2e-09 · regional, not allelic
Overall
CADD	27.7	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 0.0022% South Asian · 2/90,876 alleles

Filtering AF 0.000954% ClinGen BA1/BS1 input FAF95, joint · FAF99 0.000787%

Overall 0.0013% 21/1,612,000 alleles · very rare exomes 20/1,459,882 · genomes 1/152,118 · joint denominator

Ancestry group	Frequency	1 in
South Asiangrpmax	0.0022%	45,438
Remaining individualsnot grpmax-eligible	0.0016%	62,408
European (non-Finnish)	0.00153%	65,496

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: SRGAP1
Protein: p.Arg240Trp
Coding: c.718C>T
MANE Select: NM_020762
Type: single nucleotide variant
Location: chr12:64043492 (GRCh38)
Gene constraint: LOEUF 0.47 · pLI 1.00 (gnomAD)
Structure: AlphaFold pLDDT 73.49
Residue 240: the f-bar domain

Full SRGAP1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

thyroid cancer, nonmedullary, 2 — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

For Familial papillary or follicular thyroid carcinoma (Orphanet):

Inheritance: Not applicable
Onset: Adult

Similar variants

SRGAP1 p.Arg240Gln Uncertain significance ★ ⚠ same residue
SRGAP1 c.2225-7G>A Likely benign ★★ same condition
SRGAP1 p.Asn648Ser Uncertain significance ★ ⚠ same condition
SRGAP1 p.Gln149His Uncertain significance ★ ⚠ same condition
SRGAP1 p.Pro323Thr Uncertain significance ★ ⚠ same condition
SRGAP1 p.Thr61Met Uncertain significance ★ ⚠ same condition
SRGAP1 p.Ala275Thr Pathogenic ⚠ same condition
SRGAP1 p.Leu245fs Uncertain significance ★ same condition

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/srgap1-p-arg240trp (accessed [today's date]).

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